EA002482B1 - Sertraline salts and sustained-release dosage forms of sertraline - Google Patents

Abstract

1. A sustained-release dosage form suitable for oral administration to a mammal, comprising sertraline, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier which dosage form releases sertraline into a use environment at a rate not exceeding 0.8 mgA/hr/kg, provided said dosage form (1) releases not more than 70% of the sertraline contained therein within the first hour following entry into said use environment and (2) releases sertraline at a rate of at least 0.02 mgA/hr/kg. 2. A dosage form as defined in claim 1, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 3. A dosage form as defined in claim 1, wherein said mammal is a human. 4. A dosage form as defined in claim 1, in the form of a matrix tablet which remains substantially intact during the period of sustained release. 5. A dosage form as defined in claim 1, in the form of a disintegrating matrix tablet. 6. A dosage form as defined in claim 1, in the form of a matrix tablet partially coated with a polymer which impedes the release of sertraline. 7. A dosage form as defined in claim 1, in the form of an osmotic tablet. 8. A dosage form as defined in claim 1, in the form of a membranecoated hydrogel tablet. 9. A dosage form as defined in claim 1, which is multiparticulate. 10. A dosage form as defined in claim 1, in the form of a membranecoated diffusion-based, capsule, tablet or multiparticulate. 11. A sustained-release dosage form suitable for administration to a mammal, comprising sertraline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which dosage form releases sertraline into a use environment at a rate not exceeding 40 mgA/hr, provided said dosage form (1) releases not more than 70% of the sertraline contained therein within the first hour following entry into said use environment and (2) releases sertraline at a rate of at least 1 mgA/hr. 12. A dosage form as defined in claim 11 wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 13. A dosage form as defined in claim 11, wherein said mammal is a human. 14. A dosage form as defined in claim 11, in the form of a matrix tablet which remains substantially intact during the period of sustained release. 15. A dosage form as defined in claim 11, in the form of a disintegrating matrix tablet. 16. A dosage form as defined in claim 11, in the form of a matrix tablet partially coated with a polymer which impedes the release of sertraline. 17. A dosage form as defined in claim 11, in the form of an osmotic tablet. 18. A dosage form as defined in claim 11, in the form of a membranecoated hydrogel tablet. 19. A dosage form as defined in claim It, which is multiparticulate. 20. A dosage form as defined in claim 11, in the form of a membranecoated fiffusion-based tablet or multiparticulate. 21. A sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form releases sertraline at a rate less than 40 mgA/hr in vitro when dissolution tested in a USP-2 apparatus containing 900 ml of acetate buffer, pH 4.0, which is 0.075 M in NaCI, as follows: (1) if said dosage form is a sustained release tablet or a nontisintegrating sustained release capsule, said USP-2 apparatus is equipped with a paddle stirring at 50 rpm; (2) if said dosage form is a multiparticulate, said USP-2 apparatus is equipped with a paddle stirring at 100 rpm; provided said dosage form (a) releases not more than 70% of the sertraline contained therein within the first hour following initiation of testing and (b) releases sertraline at a rate of at least 1 mgA/hr. 22. A dosage form as defined in claim 21, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 23. A dosage form as defined in claim 21, wherein said mammal is a human. 24. A dosage form as defined in claim 21, in the form of a matrix tablet which remains substantially intact during the period of sustained release. 25. A dosage form as defined in claim 21, in the form of a disintegrating matrix tablet. 26. A dosage form as defined in claim 21, in the form of a matrix tablet partially coated with a polymer which impedes the release of sertraline. 27. A dosage form as defined in claim 21, in the form of an osmotic tablet. 28. A dosage form as defined in claim 21, in the form of a membranecoated hydrogel tablet. 29. A dosage form as defined in claim 21, which is multiparticulate. 30. A dosage form as defined in claim 21, in the form of a membranecoated diffusion-based tablet or multiparticulate. 31. A temporally delayed plus sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, following ingestion by said mammal, releases sertraline into said mammal's Gl tract at a rate less than 1 mgA/hr for an initial delay period of up to 3 hours, and which thereafter releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr, provided said dosage form releases not more than 70 % of the sertraline contained therein within the first hour after said delay period. 32. A dosage form as defined in claim 31, wherein said delay period is up to two hours. 33. A dosage form as defined in claim 31, wherein the rate of release following said delay period is from 1 mgA/hr to 30 mgA/hr. 34. A dosage form as defined in claim 31, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 35. A dosage form as defined in claim 31, wherein said mammal is a human. 36. A temporally delayed plus sustained release dosage form suitable for administration to a mammal, said dosage form having an initial temporal delay period of up to 3 hours, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, when dissolution tested in vitro in a USP-2 apparatus containing 900 ml of acetate buffer, pH 4.0, which is 0.075 M in NaCI, releases sertraline at a rate less than 1 mgA/hr for a period corresponding to said delay period and, thereafter, releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr, provided the dosage form releases not more than 70 % of the remaining sertraline contained therein within the first hour following said delay. 37. A dosage form as defined in claim 36, wherein said delay period is up to two hours. 38. A dosage form as defined in claim 36, wherein the rate of release following said delay period is from 1 mgA/hr to 30 mgA/hr. 39. A dosage form as defined in claim 36, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 40. A dosage form as defined in claim 36, wherein said mammal is a human. 41. A dosage form as defined in claim 36, in the form of a tablet. 42. A dosage form as defined in claim 36, which is multiparticulate. 43. A spatially delayed plus sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, following ingestion by said mammal, releases sertraline into said mammal's stomach at a rate less than 1 mgAlhr, and which, after having passed into said mammal's small intestine, effects sustained release at a rate of from 1 mgA/hr to 40 mgA/hr, provided said dosage form releases not more than 70 % of the sertraline contained therein within the first hour after passing into said mammal's small intestine. 44. A dosage form as defined in claim 43, wherein the onset of sustained release is pH-triggered. 45. A dosage form as defined in claim 44, comprising a sustained release dosage form coated with a polymer that prevents release of sertraline at the pH of the stomach, but which is permeable to sertraline at the pH of the small intestine. 46. A dosage form as defined in claim 44, wherein said sustained release dosage form is multiparticulate. 47. A dosage form as defined in claim 44 wherein said sustained release dosage form is a tablet. 48. A dosage form as defined in claim 43, which is enzyme-triggered. 49. A dosage form as defined in claim 48, comprising a sustained release dosage form coated with a membrane having a hydrophobic liquid entrained within the pores thereof, said hydrophobic liquid being substantially impermeable to water and sertraline, but capable of changing, through enzymatic degradation, so that said membrane becomes substantially permeable to water and sertraline when said dosage form moves into the environment of the small intestinal lumen. 50. A dosage form as defined in claim 48, wherein said sustained release dosage form is multiparticulate. 51. A dosage form as defined in claim 48, wherein said sustained release dosage form is a matrix. 52. A dosage form as defined in claim 43, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 53. A dosage form as defined in claim 43, wherein said mammal is a human. 54. A sustained release pH-triggered dosage form suitable for oral administration to a mammal, said dosage form having an initial delay period prior to the onset of sustained release, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, when tested in vitro in a USP-2 apparatus, releases sertraline into 0.1 N HCI at a rate less than 1 mgA/hr for 1 hou

Description

This invention relates to certain salts of sertraline, to a sustained release dosage form of sertraline having lower side effects and to a method for treating a psychiatric or other disease in which, if necessary, such treatment is administered to a mammal, including a human patient, sertraline in such a dosage form with prolonged release.

BACKGROUND OF THE INVENTION

Sertraline is a selective serotonin reuptake blocker (SSBL), which is particularly suitable as an antidepressant and anorexic drug and in the treatment of obsessive-compulsive disorder, premenstrual dysphoria disorder, post-traumatic stress disorder, and chemical addiction , disorders associated with the pathological state of anxiety, panic and premature ejaculation. Each of I8 4536518, published international application GSO 92/18005, I8 5130338, I8 4971998, published international application GSO 92/00103, I8 5061728, I8 4940731 and I8 4962128, is incorporated into this invention by reference. Sertraline, also known as (18-cie) -4- (3,4-dichlorophenyl) 1,2,3,4-tetrahydro-Ν -methyl-1-naphthalene amine, has the empirical formula C1 ₂ H ₁₇ ES1 ₂ and the structural formula n, mmsn, n '

C1

Sertraline is usually prescribed for the treatment of depressive illness in the usual dose range of 50 to 200 mg / day. Sertraline has a half-life of 23 hours and is taken once a day.

Patients usually start taking sertraline at a dose of 50 mg / day. Patients who do not respond to a dose of 50 mg are given higher doses. Usually, whenever possible, avoiding the start of doses in excess of 50 mg, since it is assumed that side effects such as dizziness, tremor and sweating, and gastrointestinal upset, will be more severe at higher doses. If efficacy is needed, higher doses can be achieved by titration, starting with lower doses. Improved dosage forms of sertraline, which exhibit a lower frequency and / or severity of side effects, will be useful because (1) patient comfort will improve and (2) medication can be started with doses in excess of 50 mg without the need for dose titration. On the other hand, it may be useful to start taking it at higher doses, if possible by implementing a shorter onset of antidepressant action. Thus, such an improved dosage form of sertraline, which allows oral administration of high doses of sertraline (for example, 200 mg and higher) with relatively reduced side effects, makes it possible for a wider therapeutic use of sertraline treatment and, accordingly, will provide a significant improvement in compliance taking medication and convenience. Also, an improved dosage form that reduces the frequency and / or severity of side effects at lower doses will also be significant.

Summary of the invention

The present invention provides a sustained release oral dosage form that reduces the frequency and / or severity of gastrointestinal and / or other side effects, such as dizziness, tremors and sweating, compared to currently available tablet dosage forms with immediate release of sertraline, which deliver an equivalent loading dose. The dosage form acts due to the fact that it releases sertraline at a sufficiently slow speed in order to reduce the intensity of side effects.

Dosage forms that release more than 70% of their sertraline within one hour or less than one hour are not sustained release dosage forms and do not form any part of this invention. This property therefore excludes from the invention immediate release dosage forms containing 40 mg or less than 40 mg of sertraline. Such dosage forms will technically release sertraline at a rate of less than 40 mgA / h, but are excluded from the invention because they do not provide sustained release.

In a first aspect, the invention provides a sustained release dosage form suitable for administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, the dosage form releasing sertraline into the medium in which it is used at a rate not exceeding 0.8 mgA / h / kg, preferably at a rate not exceeding 0.7 mgA / h / kg, the proposed dosage form (1) releases no more than 70% of it contained rtralina within the first hour following entry into said medium, wherein the use is performed, and (2) releases sertraline at a rate of at least 0.02 mgA / hr / kg. This aspect of the invention describes a dosage form without considering the size of any particular mammal.

In a further aspect, the present invention provides a sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, the dosage form releasing sertraline into the medium in which it is used at a rate not exceeding 40 mgA / h, the proposed specified dosage form (1) releases no more than 70% of the sertraline contained in it within the first hour after entering dilution in the specified environment in which the use is carried out, and (2) releases sertraline at a rate of at least 1 mgA / h. This aspect of the invention describes a dosage form suitable for administration to mammals, such as medium-sized adults. Thus, the dosage form of this invention releases sertraline at a rate of from 1 to 40 mgA / h. Separate ranges of release rates include rates of 2 to 40 mgA / h, 3 to 40 mgA / h, 1 to 30 mgA / h, 2 to 30 mgA / h, and 3 to 30 mgA / h. Ranges from 1 to 30 mgA / h and from 2 to 30 mgA / h are preferred. Ranges from 1 to 25 mgA / h and from 2 to 25 mgA / h are more preferred.

Reference to a dosage form that releases sertraline means (1) the release of sertraline in the gastrointestinal (GI) tract of a mammal after ingestion, or (2) the release of sertraline into the medium of the ίη νίΐτο test for analysis by the ίη νίΐτο test, as described below. A reference to the environment in which the use is carried out may thus be a reference to either the fluid of the gastrointestinal tract ίη νίνο or the test environment ίη νίΐτο.

Sertraline release rates lower than 25, 30 or 40 mgA / h are also within the scope of this invention and can provide even lower side effects, especially for patients weighing less than 50 kg, for example children. Thus, a sertraline release rate after administration of 7 mgA / h represents release indicators that are within the scope of this invention and may be even more effective in reducing side effects. The rate must, of course, be high enough to provide therapeutic efficacy, that is, a therapeutically sufficient amount of sertraline must be released from the dosage form before the dosage form is excreted in the feces. Accordingly, the dosage forms of this invention must release sertraline at a rate of at least 1 mgA / h.

The unit kg, as used in the present invention in the expression mgA / h / kg, refers to kilograms of body weight of the mammal being treated.

It is noted that the transit time from the mouth to the anus for non-disintegrating dosage forms (e.g., tablets or multiple particles) is approximately 24 hours. The dosage forms of this invention release at least 60%, preferably at least 70%, of the contained they have sertraline for 24 hours. Absorption of sertraline from the lower gastrointestinal (GI) tract, especially from the colon, is less effective than absorption from the upper GI tract, i.e. from the small intestine, as shown in Example 3. Accordingly, the delivery of less sertraline to the lower gastrointestinal tract and more sertraline to the upper gastrointestinal tract is therapeutically beneficial. Accordingly, the controlled release dosage forms of sertraline according to the invention release at least 60%, preferably at least 70% of the sertraline contained therein within 24 hours, preferably within 18 hours, most preferably within 16 hours

Although the dosage forms, as defined above, usually release at least 70% of the sertraline contained in them within 24 hours, the dosage form according to this invention can release essentially all of the sertraline contained therein much earlier than 24 hours, provided that it on the other hand, releases sertraline at a rate not exceeding 40 mgA / h or 0.8 mgA / kg / h.

The term administration, as used in this invention, is essentially a synonym for the term ingestion.

The present invention is particularly suitable for administering relatively large amounts of sertraline to a patient. The amount of sertraline contained in the dosage form is preferably at least 10 mgA, and may be 500 mgA or more. The amount contained in the dosage form is more preferably 25 to 400 mgA. The dosage form may be a single or fractional, for example consisting of two or more than two units (such as capsules or tablets, which, taken together, make up the dosage form), which are taken simultaneously or approximately simultaneously.

Sertraline can be used in the dosage forms of this invention in the form of its pharmaceutically acceptable salts and also in anhydrous as well as hydrated forms. All such forms may be used within the scope of this invention. Sertraline used is preferably a free base, salts of hydrochloride, aspartate, acetate or lactate. For convenience and consistency, reference to sertraline in terms of therapeutic amounts or rates of release in the claims refers to active sertraline, abbreviated herein as mgA, i.e. to sertraline, which is not a salt, which is an unhydrated free base having a molecular weight of 306.2. Amounts expressed in mgA can conveniently be converted to equivalent weights regardless of which salt form is desired.

The dosage forms that make up the subject of this invention are, as mentioned, sustained release formulations. A dosage form can be presented in the form of a tablet, capsule, in the form of a plurality of particles, in the form of a plurality of particles in a tablet or capsule, or in a unit dose packet (sometimes referred to in the art as a sachet). Also included in this invention are combination dosage forms, for example, those that include one or more than one sustained release tablet contained within the capsule shell, such as a gelatin capsule shell.

The term tablet is intended to encompass compressed tablets, coated tablets, matrix tablets, osmotic tablets, and other forms known in the art, and more fully disclosed and described below.

The term capsule is intended to encompass capsules in which the capsule body disintegrates after administration to release particles in the form of particles that represent the desired sustained release property, and also capsules in which the capsule body remains substantially intact during its stay in the gastrointestinal tract .

In a further aspect, the present invention provides a method of treating a psychiatric or other disease in which, if necessary, such a treatment is administered to a mammal, including a human patient, a therapeutically effective amount of sertraline in a sustained release oral dosage form that releases sertraline according to speed the release described above. Such diseases include diseases that, as is known in the art, can be treated with sertraline, including those diseases that were mentioned above.

In a further aspect, the invention provides a sustained release dosage form suitable for administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier that releases sertraline ίη νίίτο at a rate of less than 40 mgA / h when tested for dissolution in apparatus И8Р-2 containing a test medium comprising 900 ml of acetate buffer, pH 4.0, the concentration of which according to NaCl is 0.075 M at 37 ° C, in accordance with the following:

(1) if the specified dosage form is a tablet with a long release, or non-disintegrating capsule with a long release, the apparatus I8P-2 is equipped with blades rotating at a speed of 50 rpm, or (2) if the specified dosage form is a lot of particles, said I8R-2 apparatus is equipped with blades rotating at a speed of 100 rpm;

the proposed specified dosage form (a) releases no more than 70% of the sertraline contained therein within the first hour after the start of testing and (b) releases sertraline at a rate of at least 1 mgA / h.

Examples of dosage forms that fall into the category (1) above include:

a) tablets with a sustained release reservoir, such as coated diffusion tablets, osmotic tablets, and membrane-coated tablets containing a swelling hydrogel.

b) matrix tablets, both disintegrating and non-disintegrating, and

c) non-disintegrating capsules; the capsule shell material should be a non-gelatin polymer, such as ethyl cellulose or cellulose acetate.

Examples of dosage forms that fall into category (2) above include unit dose sachets (also known as sachets in the art) and powders for oral suspension. Ideally, each particle in a plurality of particles constitutes a unit having its own content, with sustained release. Larger units can be formed from particles by compression into a larger unit, similar to a tablet, which is more convenient for swallowing. However, larger units quickly disintegrate after melting, giving rise to a multiple-particle form.

It is noted that the term “plurality of particles” means a plurality of particles in which each particle is designed to provide controlled release of sertraline. Ideally, each particle in a plurality of particles constitutes a unit having its own content with sustained release. Larger units can be formed from particles. Particles in the plurality of particles each include sertraline and one or more than one excipient, as required for manufacture and operation. The size of individual particles is usually from about 50 microns to about 3 mm.

A plurality of particles, predominantly consisting of particles whose size approaches the lower limit of this size range, is sometimes referred to as a powder in this invention. Many particles, mainly consisting of particles whose size approaches the upper limit of this size range, are sometimes referred to as granules in this invention. Granules having a size outside this range may also be suitable.

Any of the dosage forms in (1) or (2) above can be enclosed in a gelatin capsule. If the dosage form is a gelatin capsule or, alternatively, coated with gelatin, then the dosage form is suitably tested in an I8P-2 apparatus equipped with blades as described in (1) or (2), depending on the particular dosage form, but with trypsin added to acetate buffer to a concentration of 0.1 mg / ml. Typically, the amount or size of the test dosage form should be such that the dosage form contains or is equivalent to 200 mgA or less of sertraline. If the dosage form contains more than 200 mgA, then the amount of the test medium based on acetate buffer should be proportionally increased.

The test solution used above is a buffer solution of acetic acid / acetate, pH 4.0, the concentration of which in No. 1C1 is 0.075 M and which is designed to simulate gastrointestinal fluids. The test solution is prepared as follows: a 0.13 M solution of acetic acid in water is prepared, and then acetic acid / acetate buffer is prepared based on this solution, adding potassium hydroxide, usually in the form of a 0.5 M aqueous solution, until a pH of 4.0 is reached. Then, sodium chloride is added in an amount sufficient to prepare a solution in No. 1C1 with a concentration of 0.075 M. The temperature of the test solution is maintained at 37 ° C during the entire dissolution test.

The release rate ίη νίίτο is determined by multiplying the contained dose by 0.8, and dividing this number by the measured time during which 80% of the contained dose is released and dissolved, as will be discussed below. If 80% of the contained sertraline is not released within 24 hours, then the amount of mgA of sertraline released by 24 hours should be divided by 24 hours in order to obtain a release rate. In addition, no more than 40 mgA is released within any one hour. This aspect of the invention thus determines a sustained release dosage form using a conveniently performed ίη νίίτο test carried out in a standard, well-known apparatus. As previously mentioned, no more than 40 mgA should be released during any one hour of the test. It is noted that the I8R-2 apparatus, equipped with blades, is well known and is described in Ipyeb 81a1e5 Ryattasoroyaa XXIII (I8R) Ωίδδοίυΐίοη TeCh S11ar1sg 711, Arrata Fk 2.

A single dosage form is tested for dissolution by placing it in an I8P-2 apparatus equipped with blades rotating at a speed of 50 rpm, containing 900 ml of the test solution described above having a temperature of 37 ° C. If the dosage form is a capsule, it is tested in the same manner except that trypsin is added to the test solution to a concentration of 0.1 mg / ml. Filtered aliquots (usually 2 or 10 ml) of the solvent medium are taken at various points in time, referred to as sampling points in this invention. The exact point in time when an aliquot is taken is not particularly important, although sampling points can be standardized for convenience. An aliquot is filtered and the sertraline content is determined using an HPLC assay or other suitable assay. Data are plotted as mgA of released sertraline (active sertraline) (or% of released sertraline base) on the Y axis versus time on the X axis. The point in time is indicated at which 80% of the sertraline dose is released.

In order to ensure the accuracy of the results, more than one, for example three or more, preferably six separate dissolution tests, should be carried out and the rates determined and averaged.

As mentioned above, the release rate ίη νίίτο is calculated from the dissolution test by dividing the amount of sertraline corresponding to 80% release (determined by multiplying the contained dose by 0.8) by the time it takes to achieve 80% release. For example, if 100 mgA of sertraline dosage form is tested in this way for oral administration, and 80% of the sertraline contained in it is released within 8 hours, then the rate of release of sertraline is (100 mg x 0.8) / 8 hours, or 10 mgA / h . Thus, this dosage form is within the scope of this invention. As another example, if 50 mgA of a sertraline dosage form for oral administration is tested ίη νίίτο, and 80% of the sertraline contained therein (in the form of a sertraline base) is released within 0.4 hours, then the release rate is (50 mg x 0.8 ) / 0.4 h, or 100 mgA / h, and the dosage form will not be within the scope of this invention.

Although there are many ways to describe the rate of release of a drug from the ίη νίίτο dosage form (e.g., first-order rate constant, zero-order rate constant, initial rate, etc.), the method described above offers an understandable test that does not depend on the release mechanism sertraline from the dosage form.

It is noted that the immediate release dosage forms of sertraline are known and commercially available (ΖοΙοΓί®, registered trademark ΡΓί / cr 1ps) in the form of solid tablets containing 50 mgA and 100 mgA. When tablets ΖΟΕΟΡΤ containing 50 mgA were evaluated using the dissolution test ίη νίίτο described above, by 0.7 hours after the start of the dissolution test, an average of 80% of sertraline was released (i.e., dissolved in the test liquid). Thus, an immediate-release tablet containing 50 mgA released sertraline at a rate of 57 mgA / h, calculated by the method described above. When two ΖΟΕΟΡΤ tablets containing 100 mgA (total dose 200 mgA) were evaluated using the above dissolution test, 80% of the sertraline was released by 1.2 hours after the start of the test. Thus, each tablet containing 100 mgA released sertraline at a rate of 67 mg / h, and for a dose of 200 mg the release was 134 mg / h, calculated by the method described above. Thus, as the ίη νίίτο test described above shows, such dosage forms are outside the scope of this invention.

In a further aspect, the present invention provides a sustained release sertraline dosage form suitable for oral administration to a mammal, which results in a maximum plasma sertraline concentration, C _max , which is less than 80% of C _max , determined when the equivalent dose of sertraline is orally administered in the form of an immediate release bolus (such as an immediate release tablet). This aspect of the invention defines a sustained release dosage form of the invention using a suitable ίη νίνο test, which is carried out on mammalian species of interest. For example, to test whether a dosage form for oral administration with a prolonged release of sertraline reduces the side effects in humans, the test dosage form of sertraline is taken by half of the group of 12 or more than 12 people and after a suitable washout period (for example, 1 week ) the same subjects take a loading dose with immediate release of the same force. The other half of the group initially receives an immediate release loading dose, followed by the test dosage form of sertraline (sustained release), and plasma sertraline levels are measured as a function of time. After determining C _max for each individual with each exposure, determine the average C _max . If C _max for a test dosage form with a prolonged release of sertraline is less than 80% of C _max for a loading dose, the test dosage form provides a decrease in the intensity of side effects compared with a bolus dosage form and is within the scope of the invention. In this embodiment, the dosage form may be a sustained release dosage form designed with or without an initial retardation period, as disclosed below. It is noted that immediate release means that no agent has been designed in the bolus to slow disintegration or dissolve the dosage form.

Dosage forms that pass either the ίη νίίτο test related thereto as described in this invention or the ίη νίνο test related thereto as described in this invention (including the C _max test described above) are within the scope of the invention, as well like dosage forms that pass all such tests related to it.

As indicated above, sustained-release dosage forms of sertraline provide a reduced C _max compared to C _max for immediate-release dosage forms containing equal amounts of sertraline. That is, the sustained release dosage forms exhibit a C _max that is less than or equal to 80% of the C _max provided by the equivalent immediate release dose. Preferred dosage forms further provide the overall effect of the drug on the blood, which, in addition, in comparison with equivalent immediate release dosage forms, does not proportionally decrease as much as Smake's sustained release. The total effect of the drug on the blood is determined in the form of PPC, the area under the curve, determined by plotting the concentration of the drug in the plasma (Y axis) versus time (X axis). AUC is usually an average, and can, for example, be averaged over all subjects in the cross-sectional study described above. Determination of PEP is a well-known procedure and is described, for example, in Ryattasoktebsk; Rgosekkek apb Ma1yetabsk, Re1eg ^ eSpd (AS8 Mopodtary 185, Ateg. Syet. 8oc., ^ Ak. E.S .; 1986). For example, it is believed that the formulation A sustained release formulation containing 100 mgA sertraline, exhibit relishes, which is 65% of _a x Refer provided an immediate release bolus containing 100 mgA of sertraline. In a preferred embodiment, sustained release dosage form A also exhibits an AUC that is higher than 65% of the AUC provided by the bolus.

In a further aspect, the invention provides a sustained release sertraline dosage form that exhibits an initial slowdown in sertraline release when the dosage form enters the medium in which it is used, i.e. after administration followed by a prolonged release of sertraline, as described above. During the retardation period, sertraline is not substantially released, although sertraline is not substantially released includes very low release rates of less than 1 mgA / h. This type of dosage form is sometimes referred to herein as a sustained release dosage form followed by a sustained release. The inventors have demonstrated that some side effects of sertraline, namely nausea, belching and diarrhea, are partially or mainly mediated by direct contact of sertraline with the upper gastrointestinal tract, mainly with the stomach, rather than mediated systemically, that is, through the action of sertraline on blood flow after absorption. The locally mediated nature of these three side effects of sertraline was not known before the clinical studies conducted by the inventors in humans (presented below as example 6). Thus, advantageous dosage forms of sertraline according to this invention include dosage forms that exhibit a spatial slowdown in the release of sertraline or a slower release in time after administration. Sertraline sustained release dosage forms that exhibit spatial retardation include dosage forms that are sensitive to their location along the gastrointestinal tract, that are time independent and that have a mechanism that largely or completely prevents the release of sertraline in the stomach, and which then begin prolonged release after the dosage form passes into the duodenum. As soon as the prolonged release of sertraline begins, it is limited in speed and extent, as described above for dosage forms with prolonged immediate release of sertraline. The spatially delayed sustained release dosage forms of the present invention begin the sustained release of sertraline within about 30 minutes, preferably about 15 minutes, after passing from the stomach to the duodenum.

Dosage forms with a prolonged release of sertraline with a time delay according to this invention are dosage forms that, after administration, exhibit a time delay before the start of a prolonged release of sertraline. By time dilation in this context is meant a delay after administration that is not associated with the spatial localization of the dosage form in the gastrointestinal tract. Dosage forms with prolonged release of sertraline with a time delay show a slowdown of up to 3 hours after administration, preferably up to 2 hours, most preferably up to 1.5 hours. This time delay minimizes the effects of sertraline after oral administration to the upper gastrointestinal tract , especially on the stomach, thus reducing the intensity of locally mediated side effects. After deceleration, the dosage form releases sertraline in a manner limited in speed and extent, as described above for dosage forms with sustained immediate release of sertraline.

It is noted that in the claims, a reference to a sustained release dosage form refers to a dosage form that does not have an initial delay period carried out therein. References in the claims to dosage forms having a retardation period carried out therein are specific indications, for example, as a sustained release dosage form having an initial retardation period, to a time-delayed or spatially delayed release dosage form followed by a prolonged release, or a similar formulation, such as the aforementioned dosage form, having an initial delay period.

It was noted that there is a natural slowdown period, usually no more than 15 minutes after administration, during which the dosage form is moistened, hydrated and otherwise exposed to body fluids (gastrointestinal tract), so that it can begin to dissolve and release sertraline. This typical retardation or induction period of about ten minutes during which hydration occurs is included in the retardation period designed in the dosage form, so that the retardation period can also be from about 15 minutes to 3 hours, preferably from about 15 minutes to 2 h. If the time of induction or deceleration is not more than 15 minutes, then such a release is not considered a release with a slowdown followed by a prolonged release. Most likely, this is just a sustained release.

Thus, the present invention provides a time-delayed sustained release dosage form suitable for administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form after administration to said mammals releases sertraline in the gastrointestinal tract the path of the specified mammal at a rate of less than 1 mgA / h for the initial period of retardation of up to 3 hours, prefer up to two hours, more preferably up to 1.5 hours, and then releases sertraline at a rate of 1 to 40 mgA / h, provided that the dosage form releases no more than 70% of the sertraline contained in it within the first hour after the indicated slowdown period.

The dosage form may also be a spatially delayed dosage form followed by sustained release suitable for oral administration to a mammal, including sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form after administration to said mammal releases sertraline into the stomach of said mammal with at a rate of less than 1 mgA / h, and after passing into the duodenum of the specified mammal In addition, sertraline releases at a rate of 1 to 40 mgA / h, provided that the dosage form releases no more than 70% of the sertraline contained in it within the first hour after passage into the duodenum of the specified mammal.

The following ίη νίίτο tests can be used to determine whether or not a particular dosage form is within the scope of this invention, depending on whether the onset of the sustained release component is time-delayed or has a spatial retardation.

If the dosage form is a time-delayed dosage form, then the ίη νίίτο test can be carried out in the same way as previously described for sustained release dosage forms that do not have a time delay enclosed in them. The dosage form will release sertraline at a rate of less than 1 mgA / h for a period of up to three hours or less, which corresponds to the duration of the retardation period, followed by a prolonged release of sertraline at a rate of 1 to 40 mgA / h, respectively. The conditions, the testing apparatus and the test medium may, on the other hand, be the same as for the respective dosage forms with sustained release of sertraline. Like other dosage forms, time-delayed dosage forms release no more than 70% of the remaining sertraline contained in them within the first hour after said slowdown.

If the dosage form is a spatially delayed dosage form with a pH initiation, the invention provides a pH initiated sustained release dosage form suitable for oral administration to a mammal, said dosage form having an initial delay period prior to the beginning of a sustained release, comprising sertraline or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, and the specified dosage form during its test tion ίη νίίτο in I8R-2 apparatus, releases sertraline into 0.1 N. HC1 at a rate of less than 1 mgA / h for at least 1 h, and then release sertraline in phosphate buffer, pH 6.8, containing 1% polysorbate-80, at a rate of 1 to 40 mgA / h, provided that the dosage form releases no more than 70% of the remaining sertraline contained therein within the first hour after the indicated delay.

If the dosage form is a spatial delayed dosage form with enzyme initiation, the invention provides an enzyme-initiated sustained-release oral dosage form suitable for administration to a mammal, said dosage form having an initial delay period before the long-term release starts, including sertraline or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, and the specified Leka the natural form when testing it ίη νίΐτο in the apparatus of the I8R-2 releases sertraline in 0.1n. HC1 at a rate of less than 1 mgA / h for a period of at least 1 h, and then releases sertraline at a rate of 1 to 40 mgA / h in phosphate buffer, pH 6.8, containing 1% polysorbate-80, and in the presence of an enzyme suitable for initiating the onset of the indicated sustained release, provided that the dosage form releases no more than 70% of the remaining sertraline contained therein within the first hour after the indicated delay.

In these tests, ίη νίΐτο 1 mgA / h was calculated as the average amount of sertraline released over one hour, calculated over the initial 1 hour or longer of the test period corresponding to the deceleration period.

The objective of the present invention is to reduce the frequency and severity of side effects induced by sertraline. This is especially important at high doses, for example 100 mg and higher, at which the frequency of side effects may be higher. This task, in particular, is carried out by controlling the speed and degree of exposure of sertraline to the gastrointestinal tract and the large circle of blood circulation in at least some patients taking sertraline, thereby reducing the overall frequency and severity of side effects induced by sertraline.

It has been noted that various types of sustained release dosage forms are known and commonly used in the art to reduce the frequency of administration of compounds with a short half-life and to reduce plasma concentration fluctuations, sometimes imparting improved safety / efficacy due to the avoidance of multiple peaks of drug concentration in plasma and cavities during the day. Since the excretion of sertraline from the human body is characterized by a long half-life of approximately 23 hours, however, it is unexpected that a sustained release dosage form will be of any benefit.

The present invention further provides a new and suitable salt of sertraline acetate, hereinafter referred to as sertraline acetate, pharmaceutical compositions containing sertraline acetate, methods for using sertraline acetate and methods for preparing sertraline acetate.

The present invention further provides a new and suitable salt of sertraline L-lactate, in the present invention hereinafter referred to as sertraline L-lactate, pharmaceutical compositions containing sertraline L-lactate, methods for using sertraline L-lactate and methods for preparing sertraline L-lactate.

The present invention further provides a new and suitable salt of b-aspartate of sertraline, in the present invention hereinafter referred to as b-aspartate of sertraline, pharmaceutical compositions containing b-aspartate of sertraline, methods of using b-aspartate of sertraline and methods for preparing b-aspartate of sertraline.

The fast-dissolving salt of sertraline acetate is highly soluble in water and as such is particularly suitable for use in controlled release, for example, sustained release, encapsulated solution or sustained release, dosage form of sertraline. Further, sertraline acetate has favorable mechanical properties and is chemically and physically stable. These properties make possible easy processing of sertraline in the preparation of dosage forms and result in tablets that are physically and chemically stable during storage and use.

The instant salt of sertraline L-lactate is highly soluble in water and as such is particularly suitable for use in controlled release, for example, sustained release, encapsulated solution or sustained release, dosage form of sertraline. Further, sertraline lactate has favorable mechanical properties and is chemically and physically stable. These properties make possible easy processing of sertraline in the preparation of dosage forms and result in tablets that are physically and chemically stable during storage and use.

The rapidly dissolving salt of L-aspartate sertraline is highly soluble in water, and as such is particularly suitable for use in controlled release, for example, sustained release, encapsulated solution or sustained release, dosage form of sertraline.

Thus, the present invention relates, in particular, to sertraline acetate.

The present invention, in particular, relates to sertraline acetate having a crystalline structure according to the x-ray analysis shown in FIG. 1, and atomic coordinates listed in table. 40-2.

The present invention also relates to sertraline acetate 1/4 hydrate.

The present invention also relates to a method for treating anorexia in a subject suffering from anorexia or anorexia symptoms, wherein an effective amount of sertraline acetate is administered to said subject.

The present invention also relates to methods for treating impulsive disorders, such as trichotillomania, pathological gambling addiction, kleptomania and pyromania, in a subject suffering from one of said impulsive disorders, in which an effective amount of sertraline acetate is administered to said subject.

The present invention also relates to methods for treating onychophagy in a subject suffering from onychophagia, in which an effective amount of sertraline acetate is administered to said subject.

The present invention also relates to methods for treating premenstrual syndrome (also referred to in the present invention as a disorder associated with premenstrual dysphoria) in a subject suffering from premenstrual syndrome in which an effective amount of sertraline acetate is administered to said subject.

The present invention also relates to methods for treating schizophrenic psychotic disorders in a subject suffering from said mental disorders or suffering from symptoms such as a pathological state of anxiety, agitation, stress, excessive aggression, social autism or emotional autism, in which an effective amount is administered to said subject sertraline acetate.

The present invention also relates to methods for treating inflammatory disorders such as psoriasis and arthritis in a subject suffering from an inflammatory disorder or from an inflammatory disorder in which an effective amount of sertraline acetate is administered to said subject.

The present invention also relates to methods of treating conditions characterized by a hyperactive immune system, such as rheumatoid arthritis and lupus, in a subject suffering from said conditions, wherein an effective amount of sertraline acetate is administered to said subject.

The present invention also relates to methods for treating mental depression in a subject suffering from said mental depression, wherein an effective amount of sertraline acetate is administered to said subject.

The present invention also relates to methods for treating disorders associated with a pathological state of anxiety, such as a panic disorder, generalized disorder associated with a pathological state of anxiety, agoraphobia, simple phobias, social phobia, a disorder associated with post-traumatic stress, obsessive compulsive disorder and personality closure disorder in a subject suffering from one or more of these disorders associated with pathological an anxiety state in which an effective amount of sertraline acetate is administered to the indicated subject.

The present invention, in particular, relates to methods for treating disorders associated with a pathological state of anxiety, as described in the previous paragraph, wherein said disorder associated with a pathological state of anxiety is an obsessive-compulsive disorder.

The present invention also relates to methods for treating chemical dependence in a subject suffering from chemical dependence, wherein an effective amount of sertraline acetate is administered to said subject.

The present invention also relates to pharmaceutical compositions comprising sertraline acetate and a pharmaceutically acceptable carrier or diluent.

The present invention also relates to pharmaceutical compositions comprising sertraline acetate having a crystalline structure according to the x-ray analysis shown in FIG. 1, and a pharmaceutically acceptable carrier or diluent.

The present invention also relates to methods for producing sertraline acetate, in which the sertraline salt is reacted with a base in the presence of a suitable organic solvent to form a free sertraline base, the indicated free sertraline base is distributed in an organic solvent, and the specified free sertraline free base is reacted with acetic acid in the presence of a suitable organic solvent.

The present invention particularly relates to methods as described in the immediately preceding paragraph, wherein said sertraline salt is sertraline hydrochloride.

The present invention more specifically relates to methods as described in the immediately preceding paragraph, wherein said solvent is hexane.

The present invention also relates to methods for producing sertraline acetate, in which the sertraline free base is reacted with acetic acid in the presence of a suitable organic solvent.

The present invention particularly relates to methods as described in the immediately preceding paragraph, wherein said solvent is hexane.

The present invention also relates to methods for producing sertraline acetate, in which the sertraline salt is reacted with a base in the presence of a suitable organic solvent to form a free sertraline base, the indicated free sertraline base is distributed in an organic solvent, and the specified free sertraline free base is reacted with acetic acid in the presence of a suitable organic solvent and isolate the specified sertraline acetate from the specified solution of Tell.

The present invention also relates to sertraline L-lactate.

The present invention in particular relates to a form of sertraline L-lactate having a crystalline structure according to the x-ray analysis shown in FIG. 3, and atomic coordinates listed in table. 48-2.

The present invention also relates to methods of treating anorexia in a subject suffering from anorexia or anorexia symptoms, in which an effective amount of sertraline L-lactate is administered to said subject.

The present invention also relates to methods for treating impulsive disorders, such as trichotillomania, pathological addiction to gambling, kleptomania and pyromania, in a subject suffering from one of these impulsive disorders, in which an effective amount of sertraline L-lactate is administered to said subject.

The present invention also relates to methods for treating premenstrual syndrome in a subject suffering from premenstrual syndrome, in which an effective amount of sertraline L-lactate is administered to said subject.

The present invention also relates to methods for treating onychophagy in a subject suffering from onychophagia, wherein an effective amount of sertraline L-lactate is administered to said subject.

The present invention also relates to methods for treating schizophrenic psychotic disorders in a subject suffering from said psychotic disorders or suffering from symptoms such as a pathological state of anxiety, agitation, stress, excessive aggression, social autism or emotional autism, in which an effective subject is administered to said subject the amount of sertraline L-lactate.

The present invention also relates to methods of treating inflammatory disorders such as psoriasis and arthritis in a subject suffering from an inflammatory disorder or from an inflammatory disorder in which an effective amount of sertraline L-lactate is administered to said subject.

The present invention also relates to methods for treating conditions characterized by a hyperactive immune system, such as rheumatoid arthritis and lupus, in a subject suffering from said conditions in which an effective amount of sertraline L-lactate is administered to said subject.

The present invention also relates to methods for treating mental depression in a subject suffering from said mental depression, wherein an effective amount of sertraline L-lactate is administered to said subject.

The present invention also relates to methods of treating disorders associated with a pathological state of anxiety, such as a panic disorder, generalized disorder associated with a pathological state of anxiety, agoraphobia, simple phobias, social phobia, a post-traumatic stress disorder, obsessive-compulsive a personality disorder disorder and disorder in a subject suffering from one or more of these disorders associated with a pathological condition Toyan anxiety, comprising administering to said subject an effective amount of sertraline L-lactate.

The present invention in particular relates to methods for treating disorders associated with a pathological state of anxiety, as described in the previous paragraph, wherein said disorder associated with a pathological state of anxiety is an obsessive-compulsive disorder.

The present invention also relates to methods for treating chemical dependence in a subject suffering from chemical dependence, wherein an effective amount of sertraline L-lactate is administered to said subject.

The present invention also relates to pharmaceutical compositions comprising sertraline L-lactate and a pharmaceutically acceptable carrier or diluent.

The present invention also relates to pharmaceutical compositions comprising sertraline L-lactate having a crystalline structure according to the x-ray analysis shown in FIG. 3, and a pharmaceutically acceptable carrier or diluent.

The present invention also relates to methods for producing sertraline L-lactate, in which the sertraline salt is reacted with a base in the presence of a suitable organic solvent to form the free base of sertraline, the indicated free base of sertraline 21 is distributed in an organic solvent, and the specified free base of sertraline is reacted with b- lactic acid in the presence of a suitable organic solvent.

The present invention particularly relates to methods as described in the immediately preceding paragraph, wherein said sertraline salt is sertraline hydrochloride.

The present invention more specifically relates to methods as described in the immediately preceding paragraph, wherein said solvent is ethyl acetate.

The present invention also relates to methods for producing sertraline L-lactate, in which the sertraline mandelate is reacted with a base in the presence of a suitable organic solvent to form a free sertraline base, the indicated free sertraline base is distributed in an organic solvent, and the specified free sertraline free base is reacted with a b-milk acid.

The present invention more specifically relates to methods as described in the immediately preceding paragraph, wherein said solvent is ethyl acetate.

The present invention also relates to methods for producing sertraline L-lactate, in which the sertraline free base is reacted with L-lactic acid in the presence of a suitable organic solvent.

The present invention, in particular, relates to methods as described in the immediately preceding paragraph, wherein said solvent is ethyl acetate.

The present invention also relates to methods for producing sertraline L-lactate, in which a sertraline salt is reacted with a base in the presence of a suitable organic solvent to form a free sertraline base, said free sertraline free base is distributed in an organic solvent, and said free sertraline free base is reacted with a b-milk acid in the presence of a suitable organic solvent and the indicated sertraline L-lactate is isolated from the indicated solution creator.

The present invention also relates to sertraline L-aspartate.

The present invention also relates to methods for treating anorexia in a subject, wherein an effective amount of sertraline L-aspartate is administered to said subject.

The present invention also relates to methods for treating impulsive disorders, such as trichotillomania, pathological addiction to gambling, kleptomania and pyromania, in a subject suffering from one of these impulsive disorders, in which an effective amount of sertraline L-aspartate is administered to said subject.

The present invention also relates to methods for treating onychophagy in a subject suffering from onychophagia, wherein an effective amount of sertraline L-aspartate is administered to said subject.

The present invention also relates to methods for treating premenstrual syndrome in a subject suffering from premenstrual syndrome, in which an effective amount of sertraline L-aspartate is administered to said subject.

The present invention also relates to methods for treating schizophrenic psychotic disorders in a subject suffering from said psychotic disorders or suffering from symptoms such as a pathological state of anxiety, agitation, stress, excessive aggression, social autism or emotional autism, in which an effective subject is administered to said subject the amount of b-aspartate sertraline.

The present invention also relates to methods for treating inflammatory disorders such as psoriasis and arthritis in a subject suffering from an inflammatory disorder or from inflammatory disorders, wherein an effective amount of sertraline L-aspartate is administered to said subject.

The present invention also relates to methods for treating conditions characterized by a hyperactive immune system, such as rheumatoid arthritis and lupus, in a subject suffering from said conditions in which an effective amount of sertraline L-aspartate is administered to said subject.

The present invention also relates to methods for treating mental depression in a subject suffering from said mental depression, wherein an effective amount of sertraline L-aspartate is administered to said subject.

The present invention also relates to methods for treating disorders associated with a pathological state of anxiety, such as a panic disorder, generalized disorder associated with a pathological state of anxiety, agoraphobia, simple phobias, social phobia, a disorder associated with post-traumatic stress, obsessive-compulsive a personality disorder disorder and disorder in a subject suffering from one or more of these disorders associated with a pathological condition Toyan anxiety, comprising administering to said subject an effective amount of sertraline L-aspartate.

The present invention, in particular, relates to methods for treating disorders associated with a pathological state of anxiety, as described in the previous paragraph, wherein said disorder associated with a pathological state of anxiety is an obsessive-compulsive disorder.

The present invention also relates to methods for treating chemical dependence in a subject suffering from chemical dependence, wherein an effective amount of sertraline L-aspartate is administered to said subject.

The present invention also relates to pharmaceutical compositions comprising sertraline L-aspartate and a pharmaceutically acceptable carrier or diluent.

The present invention also relates to methods for producing b-aspartate of sertraline, in which the sertraline salt is reacted with a base in the presence of a suitable organic solvent to form a free base of sertraline, the indicated free base of sertraline is distributed in an organic solvent, and said free base of sertraline is contacted with aspartic acid in the presence of a suitable organic solvent.

The present invention, in particular, relates to methods as described in the immediately preceding paragraph, wherein said sertraline salt is sertraline hydrochloride.

The present invention more specifically relates to methods as described in the immediately preceding paragraph, wherein said solvent is hexane.

The present invention also relates to methods for producing sertraline L-aspartate, in which the sertraline free base is reacted with aspartic acid in the presence of a suitable organic solvent.

The present invention, in particular, relates to methods as described in the immediately preceding paragraph, wherein said solvent is hexane.

The present invention also relates to methods for producing b-aspartate of sertraline, in which the sertraline salt is reacted with a base in the presence of a suitable organic solvent to form a free base of sertraline, the indicated free base of sertraline is distributed in an organic solvent, and said free base of sertraline is contacted with aspartic acid in the presence of a suitable organic solvent and the indicated sertraline L-aspartate is isolated from the indicated solvent.

Brief Description of the Figures

FIG. 1 represents the crystal structure of sertraline acetate, according to x-ray crystallography of a single crystal (atomic coordinates).

FIG. 2 is a characteristic X-ray diffraction pattern showing that sertraline acetate is crystalline (vertical axis: intensity (vibration / s), horizontal axis: two theta (degrees)).

FIG. 3 represents the crystal structure of sertraline L-lactate, according to x-ray crystallography of a single crystal (atomic coordinates)

FIG. 4 is a characteristic X-ray diffraction pattern demonstrating that sertraline L-lactate is crystalline (vertical axis: intensity (vibration / s), horizontal axis: two theta (degrees)).

FIG. 5 is a characteristic X-ray diffraction pattern demonstrating that b-aspartate of sertraline is crystalline (vertical axis: intensity (vibration / s), horizontal axis: two theta (degrees)).

FIG. 6 is a graph of FC / PD, which represents the dependence of sertraline concentration in plasma on the average results of individual assessments on visual analogue scales with divisions for the study of nausea presented in the examples.

DETAILED DESCRIPTION OF THE INVENTION

Sustained release

The implementation of dosage forms with prolonged release of sertraline can be wide. For the purpose of discussion, but not limitation, many of the embodiments presented in this invention below can be grouped into classes in accordance with the design and principle of operation.

The first class of sustained release dosage forms described below are matrix systems that include but are not limited to 1) non-degradable matrices, tablets, multiple particles, and hydrogel-based systems; 2) hydrophilic degradable, dispersible or soluble matrix systems, tablets and multiple particles; and 3) coated matrix systems. The second class consists of reservoir systems in which the release of the drug is modulated by the membrane, such as capsules and tablets or a plurality of coated particles. The third class consists of systems based on the osmotic action, such as 1) bilayer tablets with a shell, 2) homogeneous core tablets with a shell; 3) a plurality of shell particles; and 4) osmotic capsules. The fourth class consists of swellable systems in which the drug is released by swelling and displacing the components of the core through a channel in the shell or surrounding shell or outer layer.

The first class includes matrix systems in which sertraline dissolves, integrates, or disperses in the matrix of another substance, which serves to slow down the release of sertraline into the aquatic environment (i.e., gastrointestinal lumen fluid). When sertraline dissolves, embeds, or disperses in this type of matrix, drug release occurs primarily from the surface of the matrix. In this way, the drug is released from the surface of the device that encloses the matrix after it diffuses through the matrix into the surrounding liquid, or when the surface of the device dissolves or breaks down, releasing the drug. In some embodiments, both mechanisms can act simultaneously. Matrix systems can be large, i.e. tablet size (approximately 1 cm), or small (less than 0.3 cm). The system can be single, it can be divided, as discussed earlier, and, as a result, consist of several subunits (for example, several tablets that make up a single dose), which are administered essentially simultaneously, it can consist of several small tablets in the composition capsules, or it may include many particles, referred to in this invention as many particles. Many particles may have numerous uses of the drug. For example, a plurality of particles can be used in the form of small granules or powder to fill the capsule shell, it can be compressed into a tablet, or it can be used by itself to mix with food (for example, ice cream) to improve taste, or as a sachet that can be dispersed in a liquid, such as fruit juice or water.

The many varieties that affect the release of sertraline from matrix devices provide significant flexibility in the design of devices from various substances, with different sizes and times of release. Examples of modifications of the indicators of the release of sertraline from specific embodiments of the examples within the scope of this invention are described in detail below.

Non-degradable matrix tablets that provide sustained release of sertraline can be prepared using the free base of sertraline and a wide range of sertraline salts such as sertraline HC1, sertraline lactate, sertraline acetate and sertraline aspartate and water-insoluble substances such as waxes, cellulose or other water insoluble polymers. Matrix materials suitable for the manufacture of these dosage forms include microcrystalline cellulose, such as Λνίοοί (registered trademark of EMC Co., PIBlabeRa, RA), including microcrystalline cellulose grades to which binders such as hydroxypropyl methylcellulose, waxes are added such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax, etc., as well as polymers such as cellulose, cellulose esters, simple cellulose ethers, poly (vinyl chloride), poly (vinyl acetate), copolymers of vinyl acetate and ethylene, polystyrene, etc. Water-soluble binders or release modifiers that can possibly be prepared in a matrix include water-soluble polymers such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, poly (Y-vinyl-2-pyrrolidinone) (PVP), poly (ethylene oxide) (PEO), poly (vinyl alcohol) (PVA), xanthan gum, carrageenan and other such natural and synthetic substances Twa. In addition, substances that act as release modifying agents include water soluble substances such as sugars or salts. Preferred water-soluble substances include lactose, sasarose, glucose and mannitol, as well as HPC, HPMC and PVP. In addition, in matrix tablets, to increase the rate of release of sertraline, increase the total amount of sertraline released, and possibly increase the absorption and therefore bioavailability of sertraline, especially from matrix preparations that release sertraline for a period of six hours or more, you can include solubilizing acid excipients such as malic acid, citric acid, erythorbic acid, ascorbic acid, adipic acid, glutamic acid, maleic acid aconitic acid and aspartic acid and solubilizing excipients such as partial glycerides, glycerides, glyceride derivatives, polyethylene glycol esters, polypropylene glycol esters, polyhydric alcohol esters, polyoxyethylene ethers, sorbitan esters, polyoxyethylene sorbitan esters saccharide esters, phospholipids, block copolymers of polyethylene oxide and polypropylene oxide and polyethylene glycols.

In addition to the components of the matrix system, the size of the matrix system can affect the rate of release of sertraline, so large matrix systems such as a tablet will generally have a composition27 different from the composition of small matrix systems, such as multiple particles, to achieve similar release rates. The effect of the size of the matrix system on the kinetics of sertraline release corresponds to the scaling property well known in the study of diffusion. To illustrate, the following table shows the coefficient of diffusion of sertraline through a matrix required to achieve a characteristic release time of 10 hours for systems with a matrix of various sizes that release sertraline via a diffusion-based mechanism (rather than destruction or in combination with a destruction mechanism) .

Radius (cm)

0.0025 (diameter 50 μm)

0.1 (diameter 2 mm)

0.5 (diameter 1 cm)

Diffusion coefficient (cm ² / s) 1.7x10 ^-10 3x10 ^-7 7x10 ^-6

The above table illustrates that the diffusion coefficients needed to achieve the intended characteristic release time can change in order of magnitude as the desired size of the device changes. Matrix materials that can be used to provide the diffusion coefficient of sertraline at the lower end of the diffusion coefficient scale are examples, such as cellulose acetate. In contrast, substances at the upper end of the scale are substances, such as polymers, which form hydrogels upon hydration. The diffusion rate for any particular device can be suitably adjusted using a substance or selected substances and matrix structure.

For the purpose of further illustrating, in order to obtain a non-destructible matrix with sustained release in a particle with a diameter of approximately 50 μm, a matrix material is likely to be a polymer material such as cellulose acetate and the like, a slowly diffusing matrix material that seeks to compensate for the property of short small particle sizes. In contrast, in order to obtain a sustained release in a large device (e.g. 1 cm), a substance that is more like a liquid (e.g. a hydrogel, see below) or with greater porosity is likely to be required. For devices of intermediate size, for example approximately 1 mm in diameter, a matrix composition with intermediate properties may be used.

It is also noted that the effective diffusion coefficient of sertraline in the matrix can be increased to the desired value by adding plasticizers, pores or pore inducing additives, as is known in the art. Slowly hydrating substances can also be used to effectively reduce the diffusion rates of sertraline, especially at times shortly after administration. In addition to changing the effective diffusion coefficient, the release rate can also be varied by incorporating more soluble salt forms (as compared to the free base), such as sertraline lactate, sertraline acetate or sertraline aspartate, or excipients such as acids and / or surface-like compounds -active substances that solubilize sertraline and minimize gelation, especially in the presence of chloride.

The next sustained release non-destructive matrix system includes sertraline dispersed in a hydrogel matrix. This embodiment differs from the hydrophilic matrix tablet discussed below in that the hydrogel of this embodiment is not a compressed tablet of a soluble or degradable granular substance, but rather is a monolithic polymer network. As is known in the art, a hydrogel is a water-swellable network polymer. Hydrogels can be prepared in numerous forms, such as droplets, tablets and many particles. By way of example, tablets may be prepared by standard methods using from 10 to 80% crosslinked polymer. In the preparation of tablets, the polymer can be crosslinked with a chemical crosslinker, such as glutaraldehyde, or with UV radiation to form a hydrogel matrix. Hydrogels are the preferred substances for matrix devices because they can be absorbed or can be prepared in such a way that they contain a fraction of large volume water, thereby allowing diffusion of the solvated drug in the matrix. The diffusion coefficients of drugs in hydrogels are typically high, and for gels that are significantly swollen in water, the diffusion coefficient of a drug in a gel can be close to that in pure water. This high diffusion coefficient allows practical release rates from relatively large devices (i.e., it is not necessary to form microparticles). Although hydrogel-based devices can be prepared, loaded with sertraline, stored, prescribed and taken in a fully hydrated state, preferably they should be stored, prescribed and taken in a dry state. In addition to stability and convenience, the intake of hydrogel-based devices in a dry state can provide good kinetics of sertraline release due to Sake II transport (i.e., a combination of hydrogel swelling and diffusion of the drug into the environment through a swollen hydrogel). Preferred hydrogel forming agents include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, and poly (ethylene oxide). Particularly preferred are poly (2-hydroxyethyl methacrylate), poly (acrylic acid), poly (methacrylic acid), poly (Y-vinyl-2-pyrrolidinone), polyvinyl alcohol) and their copolymers with each other and with hydrophobic monomers such as methyl methacrylate, vinyl acetate and the like. Hydrophilic polyurethanes containing large blocks of poly (ethylene oxide) are also preferred. Other preferred substances include hydrogels, including interpenetrating networks of polymers that can be formed by addition or polycondensation, components that can include hydrophilic and hydrophobic monomers, such as those just listed.

Non-degradable matrix tablets can be prepared by tabletting methods that are common in the pharmaceutical industry. Preferred embodiments of non-degradable matrix tablets contain from 10 to 80% sertraline, from 5 to 50% insoluble matrix substances, such as cellulose, cellulose acetate or ethyl cellulose, and optionally from 5 to 85% plasticizers, pore forming or solubilizing excipients, and possibly from about 0.25 to 2% of a tabletting lubricant, such as magnesium stearate, sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid, polyethylene glycol-8000, talc, or a mixture of magnesium stearate and sodium lauryl sulfate I. These substances can be mixed, granulated and pelletized using a variety of equipment commonly used in the pharmaceutical industry.

An indestructible plurality of matrix particles includes a plurality of particles containing sertraline, each particle comprising a mixture of sertraline with one or more excipients selected to form a matrix capable of limiting the rate of dissolution of sertraline in an aqueous medium. Matrix materials suitable for this embodiment are typically water insoluble substances such as waxes, cellulose or other water insoluble polymers. If necessary, matrix materials may possibly be prepared with water-soluble substances that can be used as binders or as permeability modifying agents. Matrix materials suitable for the manufacture of these dosage forms include microcrystalline cellulose, such as Au1ce1 (registered trademark of EMC Co., PIB1abeRaa, PA) including varieties of microcrystalline cellulose to which binders such as hydroxypropyl methylcellulose, waxes, such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax, etc., as well as synthetic polymers such as poly (vinyl chloride), poly (vinyl acetate), copolymers of vinyl acetate and ethylene, polystyrene, etc. Water-soluble release modifying agents that may possibly be prepared in a matrix include water-soluble polymers such as HPC, HPMC, methyl cellulose, PVP, PEO, PVA, xanthan gum, carrageenan and others, such natural and synthetic substances. In addition, substances that act as release modifying agents include water soluble substances such as sugars or salts. Preferred water-soluble substances include lactose, sucrose, glucose and mannitol, as well as HPC, HPMC and PVP. In addition, any of the solubilizing acids or excipients of the type of surfactants mentioned above can be incorporated into a variety of matrix particles to increase the rate of release of sertraline, increase the total amount of released sertraline, and possibly increase the absorption and, therefore, bioavailability of sertraline, especially from matrix preparations that release sertraline over a period of six hours or more.

A preferred method of manufacturing multiple matrix particles is an extrusion / spheronization method. For this method, sertraline is wet granulated with a binder, extruded through a plate or a die with holes, and placed on a rotating disk. The extrudate is ideally broken into pieces that are rounded into spheres, spheroids, or rounded rods on a rotating plate. A preferred method and composition for this method involves using water to wet granulate a mixture comprising about 20 to 75% microcrystalline cellulose mixed with, respectively, about 80 to 25% sertraline.

A preferred method for manufacturing a plurality of matrix particles is a rotary granulation method.

For this method, sertraline and excipients, such as microcrystalline cellulose, are placed in a rotor bowl in a fluidized bed apparatus. The drug and excipient are fluidized, while spraying a solution that binds the drug and excipients together in granules or sets of particles. The solution that is sprayed in the fluidized bed may be water or aqueous solutions or suspensions of binders such as polyvinylpyrrolidone or hydroxypropyl methylcellulose. A preferred composition for this method may include from 10 to 80% sertraline, from 10 to 60% microcrystalline cellulose, and from 0 to 25% binder.

A further preferred method for manufacturing the plurality of matrix particles involves coating sertraline, matrix forming excipients and, if desired, release modifying or solubilizing seed excipients, such as sugar seed kernels known as ideals. Such coatings can be applied by a variety of methods known in the pharmaceutical industry, such as spray coating in a fluidized bed coating apparatus, spray-drying, and granulation methods such as fluidized bed granulation and rotary granulation. Shells may be applied from aqueous, organic, or molten solutions or suspensions.

A further preferred method for the manufacture of multiple matrix particles is the preparation of wax granules. In this method, the desired amount of sertraline is mixed with liquid wax to form a homogeneous mixture, cooled and then pushed through a sieve to form granules. Preferred matrix materials are wax substances. Hydrogenated castor oil and carnauba wax and stearyl alcohol are particularly preferred.

Another preferred method for manufacturing the plurality of matrix particles involves the use of an organic solvent to facilitate mixing of sertraline with the matrix material. This method can be used when it is desirable to use a matrix substance with an inappropriately high melting point, which, if used in the molten state, will cause decomposition of the drug or matrix substance, or result in unacceptable viscosity in the molten state, thereby preventing the mixing of sertraline with the substance matrices. Sertraline and the matrix material can be combined with a small amount of solvent to form a paste, and then pushed through a sieve to form granules, from which the solvent is then removed. Alternatively, sertraline and the matrix substance can be combined with a sufficient amount of solvent to completely dissolve the matrix substance and the resulting solution (which may contain solid drug particles) is spray dried to form a particulate dosage form. This method is preferred when the matrix material is a synthetic high molecular weight polymer, such as cellulose ether or cellulose ester. Solvents commonly used for this process include acetone, ethanol, isopropanol, ethyl acetate, and mixtures of two or more than two of them.

A further method of manufacturing a plurality of matrix particles involves the use of an aqueous solution or suspension of sertraline and matrix forming materials. The solution or suspension can be dried by spraying or spraying, or fed dropwise to a quenching bath or passed through a light chamber to initiate crosslinking of the matrix materials and hardening of the droplets. Thus, matrices can be prepared from latexes (for example, dispersed ethyl cellulose with a plasticizer such as oleic acid or with a volatile water-miscible solvent such as acetone or ethanol) by spray-drying methods. Matrices can also be prepared by this method by crosslinking a water soluble polymer or resin. For example, sodium alginate can be crosslinked by spraying in a solution containing soluble calcium salts, polyvinyl alcohol can be crosslinked by spraying in a solution containing glutaraldehyde, and di- and triacrylates can be crosslinked by UV radiation.

When multiple particles of sertraline are formed, the matrix can be mixed with compressible excipients such as lactose, microcrystalline cellulose, calcium hydrogen phosphate, and the like, and the mixture is compressed to form a tablet. Baking powder, such as sodium starch glycolate and crosslinked poly (vinyl pyrrolidone), are also suitable. The tablets prepared by this method disintegrate when they are placed in an aqueous medium (such as the gastrointestinal tract), thereby releasing a matrix of multiple particles that releases sertraline. Multiple matrix sertraline particles can also be placed in capsules, such as hard gelatine capsules.

A further embodiment of the matrix system is in the form of a tablet with a hydrophilic matrix, which ultimately dissolves or disperses in water containing sertraline and an amount of hydrophilic polymer sufficient to provide a suitable degree of control over the release of sertraline. Sertraline can be released from such matrices through diffusion, destruction or dissolution of the matrix, or a combination of these mechanisms. Hydrophilic polymers suitable for forming a hydrophilic matrix include HPMC, HPC, hydroxyethyl cellulose (HEC), PEO, PVA, xanthan gum, carbomer, carrageenan, and zooglan. The preferred substance is HPMC. Other similar hydrophilic polymers may also be used. When used, a hydrophilic substance swells in water and eventually dissolves and disperses in water. The rate of release of sertraline from hydrophilic matrix preparations can also be controlled by the amount and molecular weight of the hydrophilic polymer used.

In general, the use of more hydrophilic polymer reduces the release rate, as in the case of a polymer with a higher molecular weight. The use of a polymer with a lower molecular weight increases the rate of release. The rate of release can also be controlled using water-soluble additives, such as sugars, salts or soluble polymers. Examples of these additives are sugars such as lactose, sucrose or mannitol, salts such as No. 0'1. KC1, NaHCO ₃ , and water-soluble polymers such as PVP, low molecular weight HPC or HPMC, or methyl cellulose. In general, an increase in the proportion of soluble matter in a formulation increases the rate of release. In addition, any of the solubilizing acid excipients mentioned previously can be incorporated into matrix tablets to increase the rate of release of sertraline, increase the total amount of released sertraline and possibly increase the absorption and, therefore, bioavailability of sertraline, especially from matrix preparations that release sertraline over a period of six hours or more. A hydrophilic matrix tablet typically includes from about 10 to 90% by weight of sertraline and from about 80 to 10% by weight of the polymer.

A preferred hydrophilic matrix tablet includes, by weight, about 30 to about 80% sertraline, about 5 to about 35% HPMC, about 0 to about 35% lactose, 0 to about 15% PVP, 0 to about 20 % microcrystalline cellulose and from about 0.25 to about 2% magnesium stearate.

Mixtures of polymers and / or resins can also be used to prepare matrix hydrophilic systems. For example, homopolysaccharide resins such as galactomannans (e.g., locust bean gum or guar gum) mixed with heteropolysaccharide resins (e.g. xanthan gum or its derivatives) can provide a synergistic effect that, when functioning, provides faster formation and stiffer matrices for the release of the active agent (as described in US patents 5455046 and 5512297). Possibly, crosslinking agents such as calcium salts can be added to improve the properties of the matrix.

Preparations with a hydrophilic matrix, which eventually dissolve or disperse, can also be prepared in the form of many particles. Multiple particles with a hydrophilic matrix can be made by the methods described previously for non-destructible sets of particles with a matrix. Preferred manufacturing methods are layering of sertraline, a hydrophilic matrix material, and, if desired, release modifying agents, onto sugar seed kernels (e.g., ideals) by a spray coating method or to form multiple particles by granulation, such as rotary granulation sertraline, a hydrophilic matrix material, and, if desired, release modifying agents.

Matrix systems, as a class, often exhibit intermittent drug release from the matrix. This result may be due to the diffusion mechanism of drug release, and modifications to the geometry of the dosage form and / or coating or a partial coating of the coating of the dosage form can be used to help make the drug release rate more constant, as described in detail below.

In a further embodiment, the matrix tablet of sertraline is coated with an impermeable shell and an opening (e.g., a circular opening or a rectangular opening) is provided by which the contents of the tablet are released into the aqueous medium of the gastrointestinal tract. These incarnations correspond to the directions of the incarnations presented in i.8 4792448 by Kapab, and as described by Napkkop et al. 8s1. 77 (1988) 322-324, incorporated herein by reference. The hole is usually so large that the area of the released sertraline base composition is less than about 40% of the surface area of the device, preferably less than about 15%.

In another embodiment, the matrix tablet of sertraline is coated with an impermeable substance on a part of its surface, for example on one or both surfaces of the tablet, or on the radial surface of the tablet.

In a further embodiment, the matrix tablet of sertraline is coated with an impermeable substance, and a hole for drug transport is formed by drilling a hole through the shell. The hole may be exclusively through the shell, or may continue as a channel in the tablet.

In another embodiment, the matrix tablet of sertraline is coated with an impermeable substance, and a drug transport channel is formed by drilling a channel through the entire tablet.

In yet another embodiment, the matrix tablet of sertraline is coated with an impermeable substance, and one or more than one channel for drug transport is formed by removing one or more strips from the impermeable membrane, or by cutting one or more than one gap through the membrane, preferably on a radial surface or beveled tablets.

In yet another embodiment, the sertraline matrix tablet is cone shaped and completely coated with an impermeable substance. A channel for transporting the drug is formed by cutting off the top of the cone.

In yet another embodiment, the sertraline matrix tablet is hemispherical and completely coated with an impermeable substance. A channel for transporting the drug is formed by drilling a hole in the center of the flat surface of the hemisphere.

In yet another embodiment, the sertraline matrix tablet is shaped into a half cylinder and completely coated with an impermeable substance. A channel for transporting the drug is formed by cutting a gap through an impermeable sheath (or removing a strip from the sheath) along the axis of the half-cylinder along the center line of the flat surface of the half-cylinder.

One skilled in the art will understand that the geometric modifications of the embodiments described above can be equivalently formed in more than one way. For example, cutting or drilling to form a channel for drug transport can be achieved by other actions, such as a method that directly provides the desired partial shell.

By “impermeable substance” is meant a substance having sufficient thickness and impermeability to sertraline, so that the main part of sertraline is released through the channel rather than through the impermeable substance during the scale of the expected release of the drug (i.e. from several hours to about a day). Such a shell can be obtained by selecting a coating material with a sufficiently low diffusion coefficient for sertraline and applying it with a sufficiently thick layer. The impermeable coating materials of these embodiments include essentially all of the substances for which the diffusion coefficient for sertraline is less than about 10 ^-7 cm ² / s. It is noted that the previous diffusion coefficient may be quite sufficient to enable the release of sertraline from the matrix device, as described above. However, for a device of this type, which is currently being discussed, in which there is a macroscopic hole or channel, a substance with this diffusion coefficient is indeed not permeable to sertraline, compared with the transport of sertraline through the channel. Preferred coating materials include film forming polymers and waxes. Thermoplastic polymers such as poly (ethylene vinyl acetate copolymer), poly (vinyl chloride), ethyl cellulose and cellulose acetate are particularly preferred. These substances exhibit the desired low degree of permeability to sertraline when they are applied as coatings with a thickness of greater than about 100 microns.

A second class of sertraline sustained release dosage forms of the present invention include containment membrane systems or reservoir systems, such as a diffusion-based membrane-coated capsule, tablet, or multiple particles. Capsules, tablets, and multiple particles may all be reservoir systems, such as diffusion based membrane-coated systems. In this class, the sertraline reservoir is surrounded by a speed-limiting membrane. Sertraline passes through the membrane through mass transfer mechanisms well known in the art, including, but not limited to, dissolution in the membrane, followed by diffusion through the membrane or diffusion through pores filled with liquid in the membrane. These individual dosage forms based on a tank system can be large, as in the case of a tablet containing one large tank, or can be multiple particles, as in the case of a capsule containing many particles with a tank, each individually coated with a membrane. The shell may be non-porous, however, permeable to sertraline (for example, sertraline may diffuse directly through the membrane), or it may be porous.

Sustained release shells, as is known in the art, can be used to make membranes, especially polymer shells, such as cellulose ether or cellulose ether, acrylic polymer, or a mixture of polymers. Preferred materials include ethyl cellulose, cellulose acetate and cellulose acetate butyrate. The polymer can be applied as a solution in an organic solvent or as an aqueous dispersion or latex. The process of coating the shell can be carried out on standard equipment, such as a apparatus for applying a shell in a fluidized bed, a apparatus for applying a shell \ Uig51sg. or rotary layering apparatus.

If desired, the permeability of the shell can be adjusted by mixing two or more than two substances. A particularly suitable method for adjusting the shell porosity involves adding a predetermined amount of finely ground water-soluble material, such as sugars or salts or water-soluble polymers, to the solution or dispersion (e.g., aqueous latex) of the membrane-forming polymer used. When the dosage form after administration is in the aqueous environment of the gastrointestinal tract, these water-soluble membrane additives leach out of the membrane, freeing the pores that contribute to the release of the drug. The membrane membrane may also be modified by the addition of plasticizers, as is known in the art.

A particularly suitable variant of the method of applying the membrane membrane includes dissolving the coating polymer in a mixture of solvents selected in such a way that when the coating dries, the phase is reversed in the coated coating solution, resulting in a membrane with a porous structure. Numerous examples of this type of shell system are given in the description of the invention of European patent 0357369B1, published March 7, 1990, incorporated herein by reference.

Membrane morphology is not significant as long as the permeability properties listed in this invention are satisfied. However, specific membrane designs will have limitations on membrane morphology in order to achieve the desired permeability. The membrane may be amorphous or crystalline. It can possess any category of morphology obtained by any particular method, and can, for example, be a membrane polymerizable between phases (which includes a thin shell on a porous base, limiting the rate), a porous hydrophilic membrane, a porous hydrophobic membrane, a membrane based hydrogels, ionic membranes, and other such membrane structures that are characterized by controlled permeability to sertraline.

A suitable embodiment of the reservoir system is a capsule having a shell comprising a speed limiting membrane substance, including any of the membrane substances discussed previously and filled with a sertraline drug composition. A particular advantage of this form is that the capsule can be prepared regardless of the composition of the drug, so that the process conditions can be used to prepare the capsule, which can have a negative effect on the drug. A preferred embodiment is a capsule having a shell prepared from a porous or permeable polymer by a thermal molding process. A particularly preferred embodiment is a capsule shell in the form of an asymmetric membrane, i.e., a membrane that has a thin, dense region on one surface, and most of the thickness of which consists of a highly permeable porous substance. A preferred method for preparing capsules with an asymmetric membrane involves phase reversal when changing the solvent, in which a polymer solution applied to the capsule matrix is induced to phase separation by replacing the solvent with a miscible precipitant. Examples of asymmetric membranes suitable according to this invention are described in the aforementioned description of the invention of European patent 0357369 B1.

Tablets may also be reservoir systems. Sertraline-containing tablet cores can be prepared in a variety of ways standard in the pharmaceutical industry. These cores can be coated with a speed-controlling shell, as described above, which allows the sertraline in the reservoir (tablet core) to diffuse into the external environment through the shell at the desired speed.

Another embodiment of tank systems includes a plurality of particles in which each particle is coated with a polymer specially prepared to achieve sustained release of sertraline. Particles of multiple particles each include sertraline and one or more than one excipient, as required for manufacture and operation. The size of the individual particles, as mentioned above, is usually from about 50 microns to about 3 mm, although granules having a size outside this range may also be suitable. In general, granules include sertraline and one or more than one binder. Since it is usually desirable to formulate dosage forms that are small and easy to swallow, granules that contain a significant amount of sertraline are preferred over excipients. Binders suitable for the manufacture of these granules include microcrystalline cellulose (for example, Lu1cc1®. EMC Comp.). HPC, HPMC and related substances, or combinations thereof. In general, binders that are suitable for granulation and tabletting, such as starch, pregelatinized starch, and PVP, can also be used to prepare multiple particles.

Many sertraline particles based on a tank system can be prepared using methods well known to those skilled in the art, including, but not limited to, extrusion and spheronization methods, wet granulation, fluidized bed granulation, and rotational bed granulation. In addition, granules can also be prepared by applying a sertraline composition (drug with excipients) to a seed core (such as a perfect seed) by layering a drug, such as powder coating, or by applying a sertraline composition by spraying a solution or dispersion of sertraline in a suitable solution of a binder substances for poisoning in a fluidized bed, such as in an apparatus for applying shells \ Uig51sg. or rotary apparatus. An example of a suitable composition and method is spraying a dispersion of a sertraline / hydroxypropyl cellulose composition in water. Preferably, sertraline can be placed in an aqueous composition in which the solubility of sertraline exceeds its solubility in water.

A preferred method for manufacturing multiple particle nuclei in this embodiment is an extrusion / spheronization method as previously discussed for multiple matrix particles. The preferred method and composition for this method, in which water is used to wet granulate a mixture consisting of from about 5 to 75% microcrystalline cellulose with, respectively, from about 95 to 25% sertraline. Particularly preferred is the use of about 5 to 30% microcrystalline cellulose with, respectively, about 95 to 70% sertraline.

A preferred method for preparing multiple particle nuclei in this embodiment is a rotary granulation method, as previously discussed for multiple particle particles with a matrix.

A preferred method for preparing nuclei of multiple particles in this embodiment is a method of coating nucleic seeds with sertraline and possibly other excipients, as previously discussed for multiple matrix particles.

A sustained release shell, as is known in the art, especially polymer shells can be used to make the membrane, as previously discussed for tank systems. Suitable and preferred polymeric coating agents, equipment, and coating methods also include those previously discussed.

The rate of release of sertraline from the sets of particles with the shell can also be controlled by factors such as the composition and content of the binder of the core containing the drug, the thickness and permeability of the shell, and the ratio of surface to volume in the sets of particles. It will be understood by those skilled in the art that increasing the thickness of the shell will decrease the rate of release, while increasing the permeability of the shell or the ratio of surface to volume in sets of particles will increase the rate of release. If desired, the permeability of the shell can be adjusted by mixing two or more than two substances. Suitable series of shells include mixtures of water-insoluble and water-soluble polymers, for example ethyl cellulose and hydroxypropyl methyl cellulose, respectively. A particularly suitable shell modification is the addition of a finely divided water-soluble substance, such as sugar or salt. When placed in an aqueous medium, these water-soluble membrane additives leach out of the membrane, freeing up pores that facilitate drug delivery. The membrane membrane can also be modified by the addition of plasticizers, as is known to those skilled in the art. A particularly suitable kind of membrane membrane uses a mixture of solvents selected in such a way that when the membrane dries, phase reversal occurs in the applied coating solution, which will result in a membrane with a porous structure.

A preferred embodiment is a plurality of core particles comprising from about 50 to 95% sertraline and from 5 to 50% of one or more of one of the following: microcrystalline cellulose, PVP, HPC, and HPMC. Individual cores are either coated with an aqueous dispersion of ethyl cellulose, which dries to form a continuous film, or a cellulose acetate film containing PEG, sorbitol, or glycerin as a release modifying agent.

The third class of dosage forms for the sustained release of sertraline includes osmotic delivery devices or osmotic pumps, as they are known in the art. Osmotic pumps include a core containing an osmotically effective composition surrounded by a semipermeable membrane. The term semi-permeable in this context means that water can penetrate through the membrane, but substances dissolved in water penetrate through the membrane at a rate substantially slower than water. When used, when placed in an aqueous medium, the device absorbs water due to the osmotic activity of the core composition. Due to the semi-permeable nature of the surrounding membrane, the contents of the device (including the drug and any excipients) cannot penetrate the non-porous regions of the membrane and, driven by osmotic pressure, leave the device through an opening or channel previously created in the dosage form, or, alternatively, formed ίη zi in the gastrointestinal tract through the explosion of deliberately enclosed weaknesses in the membrane under the influence of osmotic pressure, or, alternatively, ίη zi in the dochnokishechnom tract by dissolution and removal of water-soluble pore formers, enclosed in the shell. An osmotically effective composition includes water-soluble particles that form colloidal osmotic pressure and water-swellable polymers. The drug itself (if it is highly soluble in water) can be an osmotically effective component of the mixture. Sertraline acetate and lactate having solubilities of 65 and 125 mg / ml, respectively, can provide an osmotic pressure in the range of 2-4 atmospheres (2.02-10 ⁶ - 4.05-10 ⁶ Pa), sufficient to promote some osmotic driving force. Since sertraline is a base, its solubility is usually higher at acidic pH. Therefore, the osmotic effectiveness of sertraline is facilitated by the presence of acidic buffers in the preparation. The composition of the drug can be separated from the osmotically effective components using a movable septum or piston.

Substances suitable for forming a semipermeable membrane include polyamides, polyesters and cellulose derivatives. Cellulose ethers and esters are preferred. Cellulose acetate, cellulose acetate butyrate and ethyl cellulose are particularly preferred. Particularly suitable substances include substances that spontaneously form one or more than one outlet channel either during manufacture or when placed in the environment in which the use is made. These preferred substances include porous polymers, the pores of which are formed by phase reversal during manufacture, as described below, or by dissolving a water-soluble component present in the membrane.

The class of substances that are particularly useful in the formation of semipermeable membranes for use in osmotic delivery devices is a class of porous hydrophobic polymers or vapor-permeable films, as described in US Patent Application Serial No. 08/096144, filed July 22, 1993, incorporated herein by reference. These substances are highly permeable to water, but not significantly permeable to substances dissolved in water. The high water permeability of these substances is due to the presence of numerous microscopic pores (i.e., pores that are much larger than molecular sizes). Despite their porosity, these substances are not permeable to molecules in aqueous solution, since liquid water does not moisten pores. Water in the vapor phase can easily penetrate through membranes prepared from these substances. Such membranes are also known as vapor permeable membranes.

A preferred embodiment of this class of osmotic delivery devices consists of a coated bilayer tablet. The shell of such a tablet includes a membrane permeable to water, but essentially not permeable to sertraline and the excipients contained therein. The shell contains one or more than one outlet channel in connection with a layer containing sertraline for delivery of the drug composition. The tablet core consists of two layers: one layer containing a sertraline composition (including possible osmotic agents and hydrophilic water-soluble polymers), and another layer consisting of an expanding hydrogel, with or without additional osmotic agents. This type of delivery device is illustrated in Example 20.

When placed in an aqueous medium, the tablet absorbs water through the membrane, causing the sertraline composition to form a distributable aqueous composition, and causing the hydrogel layer to expand and expel the sertraline composition, displacing the sertraline composition from the outlet channel. The sertraline composition may swell, contributing to the expulsion of sertraline from the channel. Sertraline can be delivered from this type of delivery system, either dissolved or dispersed in a composition ejected from the outlet channel.

Sertraline delivery rate is controlled by such factors as permeability and shell thickness, osmotic pressure of the sertraline-containing layer, water activity in the hydrogel layer and the surface area of the device. One skilled in the art will understand that increasing the thickness of the shell decreases the rate of release, while increasing the permeability of the shell or activity of the water in the hydrogel layer or the osmotic pressure of the layer containing sertraline or the surface area of the device increases the rate of release.

Examples of substances that are suitable for the formation of a sertraline composition, in addition to sertraline itself, include HPMC, PEO and PVP, and other pharmaceutically acceptable carriers. In addition, osmotic agents such as sugars or salts, especially sucrose, mannitol or sodium chloride, can be added. Substances that are suitable for forming a hydrogel layer include sodium carboxymethyl cellulose, poly (ethylene oxide), poly (acrylic acid), sodium polyacrylate and other high molecular weight hydrophilic substances. In addition, osmotic agents such as sugars or salts may be added. Particularly suitable are poly (ethylene oxides) having a molecular weight of from about 5,000,000 to about 7,500,000.

Substances that are suitable for forming the shell are cellulose ethers, cellulose ethers and mixed cellulose ethers. Preferred are cellulose acetate and ethyl cellulose, and optionally with PEG included as a permeability modifying component.

The outlet channel should be localized on the side of the tablet containing the sertraline composition. More than one such channel may exist. The output channel can be obtained by mechanical methods or by laser drilling, or by creating on the tablet an area that is difficult to cover, by using special machining during pressing of the tablet or by other methods. The rate of delivery of sertraline from the device can be optimized in such a way as to provide a method of delivering sertraline to a mammal for optimal therapeutic effect.

Osmotic systems can also be prepared with a homogeneous core surrounded by a semipermeable membrane membrane. As illustrated in Examples 16, 17, and 18, sertraline can be enclosed in a tablet core, which also contains other excipients that provide sufficient osmotic motive force, and possibly salt excipients, such as acids or compounds such as surfactants. The semi-permeable membrane membrane can be applied by conventional tablet coating methods, such as using a coating pan. The drug delivery channel can be applied by conventional tablet coating methods, such as using a coating pan. A drug delivery channel may then be formed in this shell by drilling a hole in the shell, either using a laser or other mechanical means. Alternatively, the channel may be formed by tearing a portion of the shell or by creating a region on the tablet that is difficult to cover, as described above.

The embodiment of the osmotic dosage forms for the sustained release of sertraline according to this invention includes an osmotic tablet containing sertraline, which is surrounded by an asymmetric membrane, where the specified asymmetric membrane has one or more than one thin dense region in addition to less dense porous regions. This type of membrane, similar to the membrane used in the reverse osmosis industry, usually provides an opportunity for higher osmotic flows of water than those that can be obtained with a dense membrane. When applied to a drug, such as a tablet, an asymmetric membrane allows for high drug flows and well-controlled sustained release of the drug. This asymmetric membrane includes a semipermeable polymer substance, that is, a substance that is permeable to water and substantially impermeable to salts and organic solutes, such as drugs (e.g., sertraline).

Substances suitable for forming a semipermeable membrane include polyamides, polyesters and cellulose derivatives. Preferred are ethers and cellulose esters. Particularly preferred are cellulose acetate, cellulose acetate butyrate and ethyl cellulose. Particularly suitable substances include substances that spontaneously form one or more than one outlet channel, either during manufacture or when placed in the environment in which the use is made. These preferred substances include porous polymers, the pores of which are formed by phase reversal during manufacture, as described above, or by dissolving a water-soluble component present in the membrane.

An asymmetric membrane is formed by phase reversal. A coating polymer, for example ethyl cellulose or cellulose acetate, is dissolved in a mixed solvent system comprising a mixture of solvents (e.g. acetone) and precipitants (e.g. water) for ethyl cellulose or cellulose acetate. The components of the mixed solvent are chosen so that the solvent (e.g. acetone) is more volatile than the precipitant (e.g. water). When a tablet is immersed in such a solution, removed and dried, the solvent component of the solvent mixture evaporates more quickly than the precipitant. This change in solvent composition during drying causes phase reversal, resulting in the deposition of the polymer on the tablet in the form of a porous solid with a thin, dense outer region. This outer region has many pores through which drug delivery can occur.

In a preferred embodiment of a tablet coated with an asymmetric membrane, the polymer / solvent / precipitant mixture is sprayed onto the tablet layer in a tablet coating apparatus, such as Egeipb HCT-60 tablet coating apparatus. In this method, the tablet is coated with thick porous regions, and with a final external thin dense region.

In the environment in which the use is made, for example, the gastrointestinal tract, water is absorbed through a semipermeable asymmetric membrane into the core of the tablet. As the soluble substance in the tablet core dissolves, an osmotic pressure gradient is created across the membrane. When the hydrostatic pressure inside the core surrounded by a membrane exceeds the pressure in the medium in which it is used (for example, the lumen of the gastrointestinal tract), the solution containing sertraline is pumped out of the dosage form through pre-created pores in the semipermeable membrane. The constant difference in osmotic pressure across the membrane results in a constant tablet, also comes out through diffusion. Some illustrative preparations of this type of device are described in examples 16, 17, 18 and 19.

In this embodiment, an asymmetric membrane coated sertraline tablet, sertraline salts are preferred due to their solubility in water. Salts of hydrochloride, aspartate, acetate and lactate are particularly preferred. Of these, salts of acetate and lactate are most preferred. It is also preferable to include one or more solubilizing excipients, ascorbic acid, erythorbic acid, citric acid, glutamic acid, aspartic acid, partial glycerides, glycerides, glyceride derivatives, polyethylene glycol esters, propylene glycol esters, polyethylene esters, polyhydric esters, polyols , sorbitan esters, polyoxyethylene sorbitan esters, saccharide esters, phospholipids, polyethylene oxide block copolymers and polypropylene oxide, and polyethylene glycols. Most preferred are solubilizing excipients, ascorbic acid, aspartic acid, glyceryl monocaprylate, glyceryl monostearate, glyceryl monolaurate and partial C8 to C10 glycerides.

Osmotic tablets can also be prepared with a core containing osmotic agents and / or solubilizing excipients, surrounded, firstly, by a layer containing the drug, and then, secondly, by a semipermeable coating. A tablet core containing osmotic agents and / or solubilizing excipients can be prepared by standard tablet methods known in the pharmaceutical industry. The drug-containing layer can be applied around the core by spray coating methods, where the solution or suspension of the drug and excipients are applied to the core of the tablet. The drug and excipients can also be layered around the tablet core by preparing a layered type using a tablet press to form a second drug containing layer around the tablet core, as described in Example 19. This type of compression coating method can be used to apply a powder coating ( solvent free) around the tablet core. The semi-permeable sheath can then be applied to the layered core in a variety of ways known in the art, such as spray coating or immersion coating methods, previously described in detail.

Another embodiment of the osmotic dosage forms for the sustained release of sertraline according to this invention consists of a plurality of particles of sertraline coated with an asymmetric membrane. Many particles containing sertraline are prepared, for example, by extrusion / spheronization or granulation in a fluidized bed or by coating ideal seeds with a shell consisting of a mixture of sertraline and a water-soluble polymer, as described above. The plurality of particles containing sertraline are then coated by spraying a polymer solution in a mixture of a solvent and a precipitant, as described above, to form a plurality of particles coated with an asymmetric membrane. The spray coating process is preferably carried out in a fluidized-bed apparatus, for example, an apparatus for coating in a fluidized bed C1aH SRCC-5. The polymer used to form the semipermeable asymmetric membrane is selected as described above for tablets coated with an asymmetric membrane. In the same way, excipients for the nuclei of multiple particles can be selected as described above for tablets coated with an asymmetric membrane.

Osmotic capsules can be prepared using the same components or similar to those described above for osmotic tablets and multiple particles. The capsule shell or part of the capsule shell may be semipermeable and prepared from the substances described above. The capsule can then be filled with either a powder or a liquid consisting of sertraline, excipients that provide osmotic potential and possibly solubilizing excipients. The capsule core can also be prepared in such a way that it has a bilayer and multilayer composition similar to the bilayer tablet described above.

A fourth class of sertraline sustained release dosage forms of this invention includes swellable tablets and multiple coated particles, as described in co-pending assigned application US No. 07/296464, filed January 12, 1989 (published as EP 378404 A2; 7 July 1990), incorporated herein by reference. Swellable coated tablets include a tablet core comprising sertraline and a swellable substance, preferably a hydrophilic polymer coated with a membrane that contains holes or pores through which the hydrophilic polymer can be extruded and carry sertraline into the aqueous medium in which it is used. Alternatively, the membrane may contain polymeric or low molecular weight water soluble pore formers that dissolve in the aqueous medium in which it is used, creating pores through which the hydrophilic polymer and sertraline can be extruded. Examples of blowing agents are water soluble polymers such as hydroxypropyl methyl cellulose and low molecular weight compounds such as glycerin, sucrose, glucose and sodium chloride. In addition, pores can be formed in the shell by drilling holes in the shell using a laser and other mechanical means. In this fourth class of sertraline sustained release dosage forms, the membrane substance may include any film-forming polymer including polymers that are water permeable or water impermeable, ensuring that the membrane deposited on the tablet core is porous or contains water-soluble blowing agents, or has a macroscopic opening for the penetration of water and the release of sertraline. Many particles (or granules) can be prepared in a similar manner with a core consisting of a swellable substance and sertraline, coated with a porous or pore-forming membrane. Embodiments of this fourth class of extended release sertraline dosage forms may also be multilayer, as described in EP 378404 A2.

Sustained-release preparations can also be prepared with a small portion of the dose that is initially released rapidly, followed by a sustained release of the remaining majority of the dose. The combined indicators of the release of sertraline in this case are in the volume of the dosage forms with a long release according to this invention, i.e. sertraline is released at a rate of less than 40 mgA / h, ensuring that said dosage form (1) releases no more than 70% of the sertraline contained therein within the first hour after administration (or the start of testing) and (2) releases sertraline at a rate of at least 1 mgA / h.

In the preparation of sertraline, it may be preferable to use a highly soluble salt, a composition that otherwise increases the solubility of sertraline, or a combination of both, collectively referred to as a highly soluble form. The following is a discussion of the causes and benefits that arise when considering drugs from the use of highly soluble forms of sertraline. Or, due to the salt form used or the particular excipients used in the dosage form, the highly soluble form must provide the solubility of sertraline with a value of at least 10 mgA / ml.

Sertraline salts or excipients that, in combination with sertraline, help to solubilize sertraline, may be useful for almost all types of sustained release dosage forms. Solubilized sertraline can increase release from the dosage form by increasing the concentration gradient for diffusion-based systems, such as matrix dosage forms and reservoir dosage forms. Solubilized sertraline can also increase delivery from osmotic dosage forms in that more soluble sertraline can increase the osmotic pressure in the core and increase the concentration of sertraline in the fluid that is pumped out or extruded from the dosage form. In addition, solubilized sertraline may benefit from sustained release formulations, facilitating absorption of the drug from the gastrointestinal tract. For example, higher concentrations of the drug in the colon may increase absorption, due to the higher concentration gradient across the wall of the colon.

Solubilization can be especially important for drugs with prolonged release of sertraline, since sertraline tends to form gels in many aqueous solutions, including solutions, such as intestinal fluids, which contain chloride ions. Sertraline gels can be formed by the simple introduction of chloridions into solutions of sertraline lactate or sertraline acetate. Such gels can be formed by the addition of acids to solutions of sertraline, such as tartaric acid, or combinations of acids and surfactants, such as succinic acid and sodium lauryl sulfate. However, solubilizing actions can provide other acids and / or compounds similar to surfactants, minimizing gel formation and providing the basis of the drug for the delivery of sertraline in aqueous solutions containing chloride ions, such as intestinal fluids.

The hardening of sertraline is unexpected, and the ability of some additives to prevent this hardening is both unexpected and unpredictable.

The slowing down of sertraline in sustained release dosage forms can be particularly detrimental in non-destructive matrix systems, reservoir systems and osmotic systems. In each of these types of sustained release formulations, the release of the drug depends on the transport of the drug through the distance within the device (matrix or coating layer) into the surrounding fluid. Drug transport can occur through diffusion or convection mechanisms. In both mechanisms, gel formation can reduce transport by an order of magnitude or more and in many cases will result in devices that exhibit incomplete release of the drug (for example, less than 70% of the total amount of drug in the drug).

Thus, it is advantageous to use methods for solubilizing sertraline in sustained release formulations. A first method for solubilizing sertraline is to prepare sertraline salts that have higher solubility, such as sertraline lactate, sertraline acetate and sertraline aspartate. Preferred salts exhibit solubilities in water that are more than 3 times the solubility of the sertraline HC1 salt, which has a solubility of about 3 mgA / ml.

Another method for solubilizing sertraline is to use an agent called a solubilizing agent in the present invention, which actually acts to increase and preferably maintain the solubility of sertraline (or its salt) in the medium in which it is used, compared with the solubility of sertraline in that the same environment in which the use is made when the solubilizing agent is not present.

Many solubilizing agents useful in this invention can be grouped into several broad categories:

1. Organic acids and salts of organic acids;

2. Incomplete glycerides, i.e. incompletely esterified derivatives of glycyrin, including monoglycerides and diglycerides;

3. Glycerides;

4. Derivatives of glycerides;

5. Polyethylene glycol esters;

6. Polypropylene glycol esters;

7. Polyhydric alcohol esters;

8. Polyoxyethylene ethers;

9. Sorbitan esters; and

10. Sorbitan esters of polyoxyethylene;

11. Salts of carbonates.

The amount of solubilizing agent to be used depends on the particular solubilizing agent.

In the case of solubilizing agents, which are organic acids, the preferred amount of solubilizer can be calculated as the ratio times the amount of sertraline used, where the ratio is the ratio of the solubility of the organic acid to the solubility of the sertraline salt: (solubility of the organic acid or salt / solubility of sertraline or salt of sertraline) x amount of sertraline, where solubility is expressed in mg / ml. The above expression is approximate, and some adjustment may be favorable for optimization. Typically, the above expression gives an amount that is plus / minus 25% of the final applied amount, although higher amounts of solubilizing agent can be included without any particular added benefit. In addition, salts of organic acids can be added to modify the pH and / or solubility of the organic acid, effectively optimizing the solubilizing effect of the agents.

For other types of solubilizing agents listed, typically the amount of solubilizing agent used in the dosage form will be from 1 to 150% by weight of the amount of sertraline used in this form, preferably from 1 to

100%, more preferably from 3 to 75%. Amounts of solubilizing agent in excess of 150% may be used, although it is believed that in most cases this will not give any particular advantage.

Examples of organic acids useful in the invention include malic, citric, erythorbic, adipic, glutamic, aspartic, maleic, aconitic and ascorbic acid. Preferred acids are citric, erythorbic, ascorbic, glutamic and aspartic. Also effective are salts of organic acids, such as salts of alkaline earth metals (magnesium, calcium) and salts of alkali metals (lithium, potassium, sodium), as well as mixtures of organic acids and their salts. Calcium salts such as calcium carbonate, calcium acetate, calcium ascorbate, calcium citrate, calcium gluconate monohydrate, calcium lactobionate, calcium glucoceptate, calcium levulinate, calcium pantothenate, calcium propionate, calcium hydrogen phosphate, and calcium sugar are preferred salts of organic acids.

Examples of compounds belonging to the other above categories are presented in table. one.

Table 1. Solubilizing Agents

Class Examples, chemical name Examples, trade designations (supplier) Incomplete glycerides Glyceryl monocapri- lat Moposarguyp® (81dta), Sarti1® MSM (HNes), 1tχνίίοι® 308 (Hb18) Incomplete glycerides C8-C10 Sarti® MSM (Ljes), 1t 742 (Hb§), 1m Glyceryl monooleate Muuego1® 18-99 (Ea§1tap), Ca1depe® OMO (Ca1depe), Sarti1® OMO (Ljes) Glyceryl monolinolino- at Muuego1® 18-92 (Ea§1tap) Glyceryl monostearate 1t \\ 11og'k. 191 (H1 §) Ca1depe® O8O (Ca1depe) Glyceryl monolaurate 1t \\ 11og'k. 312 (H1 §) Sa1depe® ORO (Ca1depe) Glyceryldilaurate Sarti1® ODA. (lyes) Glycerides Triacetin Tpaseyp (81dta) Glyceride derivatives PEG derivatives of glycerides SzetorLog® KN40, SzetorLog® KN60 (BA8P), Assopop CA5, SA-9, SA-15, GS230, TON (ANES)

Polyglycosylated Glycerides Oe1is1ge® 44/14, 42/12, 50/13, 53/10, 35/10, 48/09, 46/07, 62/05, 50/02; LaGaGo1® (Oaie Gegg); Sarti® 3OO; 3O8, 6O2O, 6O28, 10O4O, 10O10O (AlNes) Polyethylene glycol esters PEG200 monolaurate, PEG400 monolaurate, PEG600 monolaurate Ca1depe® 20-b, Ca1depe® 40-b, Ca1depe® 60-b PEG200 monostearate, PEG400 monostearate, PEG600 monostearate Ca1depe® 20-8, Ca1depe® 40-8, Ca1depe® 60-8 PEG200dilaurate, PEG400dilaurate, PEG600dilaurate Ca1depe® 22-b, Ca1depe® 42-b, Ca1depe® 62-1. Polypropylene glycol esters Propylene glycol dicaprylate Сар1ех® 200 (АННес) Polyhydric alcohol esters Diethylene glycol monolaurate Ca1depe® OCH. Propylene glycol monolaurate Ca1depe® ROME Ascorbyl palmylate Agcogu1 Ra1t11a1e (81dta) Polyoxyethylene ethers PEG lauryl ether №> shoshs R-4 (Ca1depe) PEG stearyl ether No.> shoshs 8-20 (Sa1depe), Mood 45, 52, 53, 59 (81dta) Sorbitan esters Sorbitan monolaurate Ca1depe® 8MB, 8rap® 20 (81dta) Sorbitan monooleate Sa1depe® 8MO, 8rap® 80 (81dta) Polyoxyethylene Sorbitan Esters POE- 20 sorbitan monolaurate Ca1depe® P8Mb20, 8rap® 20 (81dta), T ^ een® 20 (81dta), Sarti1® POE-b (AB11c) POE-20 monooleate T ^ ehn® 80, P8MO- twenty Saccharide esters Sucrose monolaurate Kuo1o ЕГС-1540 (Сет 8етсе) Phospholipids Phosphatidylcholine I, ec1111p1 (81dta) Mixed phospholipids Etroz P70-30C (GSYSO) Block copolymers PEO-PPO block copolymers P1igoshs® P-68, P127, P-62 (VA8P) Polyethylene lycols PEG 3350 Various sources

In addition, other compounds suitable as solubilizing agents of the invention are ethyl propionate, methyl paraben, propyl paraben, propyl gallate, niacinamide, ethyl vanillin, para-aminobenzoic acid, butylated hydroxyanisole, imidurea and glycine. It is also noted that preferred compositions include mixtures of an organic acid with or without an appropriate salt of an organic acid, and one or more inorganic solubilizers, as indicated in the above table. 1. Also indicate that it has been observed that in order to be most effective, the solubilizer must have solubility in an aqueous chloride ion containing medium in which it is intended to use at least 1 mg / ml, and preferably more than 5 mg / ml.

The preferred group of solubilizing agents, in addition to the preferred organic acids mentioned above, includes the solubilizing agents listed in the table. 2.

Table 2. Preferred Solubilizing Agents

Class Examples, chemical name Examples, trade names (source) Incomplete glycerides Glyceryl monocapri- lat Mοηοсар ^ у1 ^ η (81§t), Sarti1 MSM (Ayes), 1t \\ ί1οι®. 308 (H18) Incomplete glycerides C8-C10 Sarti®® MSM (AB | 1c), Ιιιιχχίίίίοι® 742 (НЬ1§), Ιιιιχνίίοι® 988 (НЬ18) Glyceryl monostearate Ιιιιχνίίοι®. 191 (H1 §) Ca ^ e ^ ® Ο8Θ (Ca1ae) Glyceryl monolaurate Ιιιιχνίίοι®. 312 (H1 §) Ca ^ e ^ ® OO (Ca1eie) Glycerides Triacetin Typassyp (8pcs) Sorbitan esters Sorbitan monolaurate Ca ^ e ^ ® 8Mb, 8pf1® 20 (81§ta) Sorbitan monooleate Ca ^ e ^ ® 8MO, 8рш1® 80 (8pcs) Phospholipids Phosphatidylcholine 1.EC1111P1 (8pcs) Mixed phospholipids Etp1§® I> 70-300 (νΐΐοο) Block copolymers PEO-PPO block copolymers R1igoshs® G-68, G 127, G-62 (VA8G) Polyethylene glycols PEG 3350 Various sources

Note: The commercial suppliers listed above are as follows:

ЛПсе Cons. 6αηο5νί11ο, XVI

VA8G, ΡηΐΈίρρηην. N1

SALSE SESH1SA1 1PS. ΞΚοΚίο, 1b SPet Zeptse, 1ps., Vе5ΐ THANKS RA NK Atensa, P18sa1atau, N1 81dta, 8ΐ. Ρουίδ, MO ΧνίΡο, ΗουδΙοη, TX

Preferred combinations of solubilizing agents include (1) an organic acid together with a salt of the same or a different organic acid, (2) an organic acid together with a nonionic solubilizing agent, such as any of those listed in table. 1, and (3) an organic acid together with a salt of the same or different organic acid with a nonionic solubilizing agent.

Particularly preferred individual solubilizing agents include aspartic acid, glyceryl monocaprylate, glyceryl monolaurate, calcium acetate, ascorbic acid, citric acid, glutamic acid and calcium carbonate. Aspartic acid, glyceryl monocaprilate and calcium acetate are most preferred.

Combinations of preferred acids and preferred compounds like surfactants are also preferred. A screening test suitable for testing prospective solubilizers for use with sparingly soluble sertraline salts such as sertraline hydrochloride is found in the examples below.

Preferred embodiments of sustained release formulations are osmotic systems comprising a core comprising sertraline lactate or sertraline acetate or sertraline aspartate, an acid such as ascorbic, erythorbic, citric, glutamic or aspartic acid, and, if necessary, soluble sugar as an osmotic agent, a binder, such as microcrystalline cellulose, swellable hydrophilic polymers, and a lubricant, such as magnesium stearate. More preferred embodiments include sertraline lactate or sertraline acetate.

Another preferred embodiment of sustained release preparations is osmotic systems comprising a core containing sertraline lactate or sertraline acetate, an acid such as ascorbic, erythorbic, citric, glutamic or aspartic acid, a substance like surfactants, such as incomplete glycerides, glycerides, sorbitan esters, phospholipids, block copolymers of polyethylene oxide and polypropylene oxide, and polyethylene glycols, and, if necessary, soluble sugar for osmotic pressure values in the core, swelling hydrophilic polymers, binders, such as microcrystalline cellulose, and a lubricant, such as magnesium stearate.

Another preferred embodiment of sustained release formulations is osmotic systems comprising a core containing sertraline lactate or sertraline acetate, a surfactant-like substance such as partial glycerides, glycerides, sorbitan esters, phospholipids, polyethylene oxide and polypropylene oxide block copolymers and polyethylene glycols, soluble sugar to increase the osmotic pressure in the core, and, if necessary, swelling hydrophilic polymers, binders a, such as microcrystalline cellulose, and a lubricant, such as magnesium stearate.

Preferred embodiments of sustained release formulations are osmotic systems, such as any of the three osmotic systems discussed immediately above, and also coated with an asymmetric membrane prepared by phase reversal. Sertraline lactate is particularly preferred for use in these membrane systems, as are ascorbic and aspartic acids and partial glycerides.

Slow release followed by sustained release

Since it is also an object of the present invention to reduce the effect of high concentrations of sertraline on the upper gastrointestinal tract to reduce certain side effects (e.g., nausea, diarrhea, and burping), an additional class of dosage forms includes those forms that include slowing down before prolonged release of sertraline. Such dosage forms can be described as spatial delayed dosage forms followed by a sustained release of sertraline or time-delayed dosage forms followed by a sustained release of sertraline, as described above. In principle, any sustained-release device including any of the many embodiments discussed above can be coated with an outer, usually completely covering, coating that provides a sustained release (i.e., less than 1 mgA / h) before starting a sustained release. The shell may be of a type that provides time dilation or spatial deceleration.

The first embodiment may be illustrated by a tablet including an immediate release core comprising sertraline coated with a first shell of a polymer substance of a type that is suitable for providing sustained release of sertraline from the core, and a second shell of a type that is suitable for slowing the release of drugs after taking the dosage form. The second membrane collapses and becomes permeable as soon as the tablet leaves the stomach or after a predetermined time. The first (inner) shell is applied to the tablet and surround the tablet. The second (outer or outer) shell is applied to the first shell and surround it with the first shell.

A tablet can be prepared by methods well known in the art and contains a therapeutically suitable amount of sertraline together with excipients such as are necessary for the preparation of a tablet by such methods. The second shell is a retardation shell or with a spatial slowdown, or with a slowdown in time.

The first shell may be a sustained release shell, as is known in the art, especially polymer shells for making the membrane, as previously discussed for tank systems. Suitable and preferred polymeric coating agents, equipment, and coating methods also include those discussed previously.

Substances suitable for the preparation of a second (retardant) coating on a tablet include polymers known in the art as enteric coatings for sustained release of pH initiated pharmaceutical preparations. Such membranes are not permeable to sertraline at pH of the stomach, but become permeable in the environment of the small intestine or through dissolution, decomposition, or destruction in another way, so that sertraline can freely pass through the membrane. Polymers that are pH sensitive, which are relatively insoluble and not permeable at pH of the stomach, but which are more soluble and more permeable at pH of the small and large intestines, include polyacrylamides, phthalate derivatives such as acidic carbohydrate phthalates, amylose acetate phthalate, cellulose acetate phthalate , other cellulose phthalate esters, cellulose phthalate phthalates, hydroxypropyl cellulose phthalate, hydroxypropylethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrophthalate, sodium cellulose acetate phthalate, acid starch phthalate, copolymer of styrene, maleic acid and dibutyl phthalate, cellulose acetate trimellate, copolymer of styrene, maleic acid and polyvinyl acetate copolymer, acid copolymers, copolymers of acid and polyvinyl acetate acrylic acid, polymethacrylic acid and its esters, copolymers of polyacrylic and methacrylic acids, shellac, and copolymers of vinyl acetate and crotonic acid you.

Preferred pH-sensitive polymers include shellac, phthalate derivatives, especially cellulose acetate phthalate, polyvinyl acetate phthalate and hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellate, polyacrylic acid derivatives, especially copolymers comprising acrylic acid and at least one ester of acid, polymethylmethacrylate mixed with copolymers of acrylic acid and an ester of acrylic acid, and copolymers of vinyl acetate and crotonic acid.

A particularly preferred group of pH-sensitive polymers includes cellulose acetate phthalate, polyvinyl acetate acetate 57 lat, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellate, anionic acrylic methacrylic acid and methyl methacrylate copolymers and at least one acrylic ester and at least one ester ester. .

The thickness of the shell with a slow release is adjusted to obtain the desired properties of the slowdown. In general, thicker shells are more resistant to destruction and, therefore, provide a longer deceleration. Preferred shells in thickness range from about 20 microns to about 1 mm.

After administration, the double-coated tablet passes through the stomach, in which the second shell prevents the release of sertraline (i.e., maintains the release rate of less than 1 mg / h) under the acidic conditions prevailing in the stomach. When a tablet leaves the stomach (in which some side effects can be mediated) into the small intestine, in which the pH is higher, the second membrane breaks down or dissolves in accordance with the physicochemical properties of the selected substance. When the second shell is destroyed or dissolved, the first shell prevents the immediate or rapid release of sertraline and changes the release in such a way as to prevent the formation of high concentrations, thereby minimizing side effects.

A second embodiment of a sustained release dosage form followed by a sustained release of sertraline includes a plurality of particles in which each particle is coated twice, as previously described for tablets, firstly with a polymer specially formulated to provide sustained release of sertraline and then coated with a polymer, specially obtained to slow the onset of release into the environment of the gastrointestinal tract when taking the dosage form. The granules contain sertraline and may contain one or more excipients, as appropriate for the manufacture and operation. Preferred are multiple particles that contain a significant amount of sertraline compared to a binder. The plurality of particles can be a composition and can be made by any of the methods previously described for the plurality of particles used to prepare tank systems (including extrusion and spheronization, wet granulation, fluidized bed granulation and rotary granulation, bedding, and so on).

A sustained release coating can be applied in accordance with what is known in the art. Suitable and preferred polymeric coating agents, equipment, and coating methods also include those discussed previously.

The rate of release of sertraline from multiple sustained release particle shells (i.e., multiple particles before they are coated with a sustained release shell) and shell modification methods are also controlled by factors previously discussed for the multiple particle sertraline with a reservoir system.

The second membrane or shell for multiple particles with two shells is a shell with a slow release, which is applied to the first shell with a sustained release, as described above for tablets, and can be prepared from the same substances. However, it is preferable to achieve a sustained or controlled delivery of sertraline after the sustained release shell has dissolved or collapsed, so that the benefits of this embodiment can be realized by a suitable combination of the sustained release property and the sustained release property, and part sustained release alone may or may not necessarily satisfy the standard I8P criterion for enteric coatings. The thickness of the shell with a slow release is adjusted to obtain the desired properties of the slowdown. In general, thicker shells are more resistant to destruction and, therefore, provide a longer deceleration.

A third embodiment of a sustained release dosage form followed by a sustained release of sertraline includes a core with a disintegrating or nondestructive matrix, typically coated tablets or a plurality of particles, as described above, which slows down the onset of sustained release of sertraline before the coated tablet passes out stomach into the duodenum or more distally. Polymers suitable for sustained release shells are pH sensitive polymers previously described for tablets and multiple shell coated particles with a reservoir.

Sustained release dosage forms followed by sustained release of sertraline, pH initiated, can also be prepared by coating a tablet with a matrix of either a plurality of particles or cores of an osmotic tablet or a core of a plurality of particles with a single membrane comprising a mixture of a water-insoluble film-forming polymer, preferably a semipermeable polymer, such as cellulose acetate or ethyl cellulose; and a pH sensitive polymer selected from the list above. Preferred and particularly preferred pH sensitive polymers for this embodiment are polymers which are the preferred and particularly preferred pH sensitive polymers described above. Preferred coating membranes of this embodiment include from 10 to 70% pH sensitive polymer. In general, thicker coating membranes will provide longer retardation. In general, a lower pH-sensitive polymer in the coating membrane will provide longer retardation. Slowing can also be controlled by the inclusion of less or more water-soluble polymers, such as HPMC, and low molecular weight compounds, such as glycerin, sucrose, glucose, sodium chloride, citric acid and fumaric acid. The slowdown time can be increased by choosing water-soluble membrane pore formers that have lower solubility or slower hydration. For example, citric acid as a pore former of the membrane membrane, compared with fumaric acid as a pore former of the membrane membrane, will cause a shorter retardation due to the higher solubility of citric acid.

The fourth embodiment includes osmotic dosage forms, as previously discussed in the part relating to the Sustained Release section, but which are designed to provide a retardation period of more than 15 minutes. Osmotic embodiments include bilayer tablets comprising (1) sertraline and a layer containing an osmotic agent, where the osmotic agent may be lactose, sucrose, an organic acid or base, salt or the like, (2) a second layer containing swellable a polymer, for example polyethylene oxide, and (3) a polymer shell around the entire bilayer tablet, said shell comprising preferably a semipermeable polymer, such as cellulose acetate, along one or more than one sertraline outlet, p spolagayuschegosya on the side of the tablet containing the sertraline. The retardation period can be suitably designed in the osmotic dosage form by increasing the thickness of the membrane or decreasing its porosity. Such a retardation may have therapeutic benefits, such as reduced side effects and reduced metabolic interactions with concomitantly administered drugs.

The osmotic dosage forms, which are sustained release dosage forms followed by sustained release of the present invention, include tablets and a plurality of particles with a sertraline core surrounded by a semipermeable asymmetric membrane. The tablet core contains sertraline, an osmotically effective solute, and possibly acidic solubilizers of sertraline, sertraline gel inhibitors like surfactants, swellable polymers, viscosity-modifying polymers, and other well-known pharmaceutical excipients, as appropriate. The drug itself, if it is highly soluble in water, can be an osmotically effective component of the mixture. Sertraline salts are preferred. Especially preferred are the hydrochloride, aspartate, acetate and lactate salts. Of these salts, acetate and lactate are most preferred. Sertraline acetate and lactate, having solubilities of 64 and 125 mg / ml, respectively, can provide an osmotic pressure in the range of 2-4 atmospheres (2.02-10 ⁶ - 4.05-10 ⁶ Pa), sufficient to promote some osmotic driving force.

Substances suitable for the formation of a semipermeable membrane include polyamides, polyesters and cellulose derivatives. Cellulose ethers and esters are preferred. Cellulose acetate, cellulose acetate butyrate and ethyl cellulose are particularly preferred. Particularly suitable substances include substances that spontaneously form one or more than one outlet channel either during preparation or when placed in the environment in which the use is made. These preferred substances are used to form porous membranes, the pores of which are formed by phase inversion during preparation or by dissolving a water-soluble component present in the membrane. The preparation of asymmetric semi-permeable membranes with phase reversal has been described above in this description.

In a preferred embodiment of a tablet coated with an asymmetric membrane, the polymer / solvent / precipitant mixture is sprayed onto the tablet layer in a tablet coating apparatus, such as Egeiyeb HCT-60 tablet coating apparatus. In this embodiment, the tablet is coated with thick porous regions, and with a finite external thin dense region. To form a dense area that causes retardation, the spray solution is sprayed under conditions that are quite different from the conditions causing phase reversal, which can be used to prepare tablets coated with an asymmetric membrane without a retardation period.

In the environment in which the use is made, for example, the gastrointestinal tract, water is absorbed through a semipermeable asymmetric membrane into the core of the tablet. As the soluble substance in the tablet core dissolves, an osmotic pressure gradient is created across the membrane. When the hydrostatic pressure inside the core surrounded by a membrane exceeds the pressure in the medium in which it is used (for example, the lumen of the gastrointestinal tract), the solution containing sertraline is pumped out of the dosage form through pre-created pores in the semipermeable membrane.

It is preferable to include in the core of tablets or multiple particles one or more sertraline solubilizing excipients, including ascorbic acid, erythorbic acid, citric acid, glutamic acid, aspartic acid, partial glycerides, glycerides, glyceride derivatives, polyethylene glycol esters polyhydric alcohol esters, polyoxyethylene ethers, sorbitan esters, polyoxyethylene sorbitan esters, saccharide esters, phospholip rows, block copolymers of polyethylene oxide and polypropylene oxide, and polyethylene glycols. Most preferred are solubilizing excipients, ascorbic acid, aspartic acid, glyceryl monocaprylate, glyceryl monostearate, glyceryl monolaurate and partial C ₈ -C ₁₀ glycerides.

The retardation period can be designed in such a way that it is up to 3 hours or more by selecting an asymmetric membrane composition, for example by choosing the ratio of the membrane polymer (such as cellulose acetate or ethyl cellulose) to a plasticizer (such as PEC-3350 or other water-soluble plasticizer ) An increase in membrane thickness or the ratio of membrane polymer to plasticizer results in a longer retardation time. Slowing can also be controlled by the inclusion of more or less water-soluble polymers, such as HPMC, and low molecular weight compounds like glycerin, sucrose, glucose, sodium chloride, citric acid and fumaric acid. The slowdown time can be increased by choosing water-soluble pore-forming membranes that have lower solubility or slower hydration. For example, citric acid as a pore former of the membrane membrane, compared with fumaric acid as a pore former of the membrane membrane, will cause a shorter retardation due to the higher solubility of citric acid. The retardation time can be increased by incorporating a smaller amount of precipitant in the coating solution in order to slightly deviate from the ideal phase reversal conditions. The slowdown time can be reduced by including more osmotic excipients, or excipients with higher osmotic pressure or solubilizers, in the core. Sustained release dosage forms followed by sustained release of sertraline in the form of an osmotic tablet coated with an asymmetric membrane according to this invention are illustrated in examples 17 and 18.

A fifth embodiment of a sustained release dosage form followed by a sustained release of sertraline includes swellable tablets and a plurality of coated coated hydrogel particles, as described in co-pending Assigned Application US No. 07/296464, filed January 12, 1989 (published as EP 378404 A2; July 7, 1990), incorporated herein by reference. Swellable coated tablets include a tablet core comprising sertraline and a swellable substance, preferably a hydrophilic polymer coated with a membrane that contains holes or pores through which the hydrophilic polymer can be extruded and carry sertraline into the aqueous medium in which it is used. Alternatively, the membrane may contain polymeric or low molecular weight water soluble pore formers that dissolve in the aqueous medium in which it is used, creating pores through which the hydrophilic polymer and sertraline can be extruded. Examples of blowing agents are water soluble polymers such as HPMC and low molecular weight compounds such as glycerin, sucrose, glucose, sodium chloride, citric acid and fumaric acid. In addition, pores can be formed in the shell by drilling holes in the shell using a laser and other mechanical means. In this fifth embodiment of a sustained release dosage form followed by a sustained release of sertraline, the membrane material may include any film-forming polymer including polymers that are water permeable or water impermeable, ensuring that the membrane is applied to the core tablets, is porous or contains water-soluble blowing agents, or has a macroscopic opening for the penetration of water and the release of sertraline.

For swellable tablets and a plurality of coated hydrogel particles, the preferred swellable core polymers include polyethylene oxide with a molecular weight of 3,000 to 500,000 and carboxymethyl cellulose. Preferred coating polymers include cellulose acetate and ethyl cellulose, and hydrophobic polymers such as ethylene vinyl acetate.

For swellable tablets and many coated hydrogel particles, the retardation period can be designed to be up to 3 hours or more by choosing a membrane composition, i.e. choosing the ratio of the membrane to the blowing agent. An increase in membrane thickness or the ratio of membrane polymer to plasticizer results in a longer retardation time. The slowdown time can be increased by choosing water-soluble pore-forming membranes that have lower solubility or slower hydration. For example, citric acid as a pore former of the membrane membrane, compared with fumaric acid as a pore former of the membrane membrane, will cause a shorter retardation due to the higher solubility of citric acid. The slowdown time can be reduced by incorporating a larger proportion of low molecular weight swelling polymer (for example, less than 20,000 daltons) into the core.

A sixth embodiment is an enzyme-initiated system, such as an enzyme-initiated membrane supporting membrane, of the type described in PCT / 93δ 93/07463, published XVO 94/12159 on June 9, 1994, incorporated herein by reference. This membrane is a microporous hydrophobic membrane with a hydrophobic fluid trapped in the pores of the membrane. This membrane contains a diffuse core with a matrix or an osmotically active core that is involved in controlling the release of sertraline after the dosage form leaves the stomach. The hydrophobic liquid is substantially impermeable to both the aqueous medium and the sustained release preparation in question. The hydrophobic liquid is capable of changing so that it becomes permeable to the aquatic environment. After administration of the dosage form to mammals, the release of sertraline into the gastrointestinal system slows down before the dosage form leaves the stomach and enters the duodenum. The captured hydrophobic fluid undergoes a change that is catalyzed by enzymes in the lumen of the small intestine, but not in the stomach, so that the hydrophobic fluid in the pores of the retardation membrane is destroyed, so that the membrane becomes permeable to water and sertraline. Examples of hydrophobic liquids are triglycerides, fatty anhydrides, esters of fatty acids and cholesterol, esters of hydrophobic amino acids, and the like. Preferred triglycerides include triolein, tricaprilin, trilaurin, olive oil, palm oil, coconut oil, sesame seed oil, corn oil, peanut oil, soybean oil, etc. Preferred fatty acid anhydrides include caprylic anhydride, lauric anhydride, myristic anhydride, etc. Mixtures of hydrophobic liquids may be used. bones. Examples of substances for a microporous hydrophobic support membrane include cellulose esters, polycarbonates, polyalkenes, polystyrenes, polyvinyl esters, polysiloxanes, polyacrylates and polyethers. Preferably, the hydrophobic microporous membrane, together with the entrained hydrophobic fluid, is not permeable to sertraline, before the enzymes of the gastrointestinal tract catalyze changes in the hydrophobic oil, as described below.

In the environment in which it is used, that is, in the lumen of the small intestine, lipases and esterases destroy the aforementioned hydrophobic oils, forming surface-active products in the pores of the microporous membrane of this embodiment, thus forming water channels through which sertraline in the core of the device can exit through a microporous hydrophobic supporting membrane. Once the retardation membrane becomes porous, the release of sertraline is controlled by the limitations of sustained release from the device in question or the porosity and thickness of the porous hydrophobic shell.

Hydrophobic oils, which are substrates for small intestinal proteases, such as carboxypeptidase and chymotrypsin, can be used in the enzyme-initiated support fluid retardant membrane as described above. Examples of oils are hydrophobic esters of amino acid derivatives.

In yet another embodiment of a spatial slow release dosage form followed by a sustained release of sertraline, tablets, capsules, granules or sustained-release powders of sertraline are coated with a coating that contains components that are broken down by enzymes in the lumen of the small intestine, but not in the lumen of the stomach. The shell includes natural or synthetic waxes or triglycerides that are solid at body temperature. Preferred embodiments include from 2 to 20% of a substance that is liquid at body temperature and which is broken down by small intestinal enzymes (for example, trypsin, chymotrypsin, elastase, lipase). Suitable non-enzyme resistant fluids are those described above for enzyme-supported fluid membrane devices. Preferred waxy shells are used in an amount of 3 to 20% by weight of the uncoated tablets, capsules, granules or sertraline powder.

In a seventh embodiment of a time-delayed release dosage form of sertraline, tablets, granules or particles with sustained release of sertraline are prepared and then coated with a water-soluble and / or water-disintegrating retardant layer. In preferred embodiments, disintegrating or non-disintegrating tablets or granules of sertraline with a matrix are coated with a time delay layer. Preferred retardants include hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyethylene oxide and polyvinylpyrrolidone. This shell can be applied to tablets in a tablet coating apparatus, such as an NST-30, NST-60 or NST-130 ΟοΗίβΓ apparatus, available from Prinz 1ps. The tablets are coated with an aqueous solution of HPMC or other suitable polymer to a final shell weight of 5 to 50% of the final weight of the coated tablet. Larger shell masses provide longer decelerations before the release of sertraline into the medium in which it is used, such as the lumen of the gastrointestinal tract. The slowdown time can also be increased, including poorly water-soluble polymers in the coating composition, including but not limited to ethyl cellulose (EC), cellulose acetate (AC), cellulose acetate butyrate in small to medium amounts. For example, the coating composition may consist of a mixture of 95: 5 HPMC / EC to 50:50 GPMC / EC or 95: 5 HPMC / AC to 50:50 HPMC / AC. In the case of such mixed polymer coating systems, it may be necessary to adjust the solvent composition to dissolve the mixture of water-soluble and slightly water-soluble polymers. For example, mixtures of acetone and water or ethanol and water may be used as necessary. Granules and particles can be similarly coated using a fluidized bed coater, such as a CGAI 6RS6-5 apparatus. For granules, the shell is from 10 to 100% by weight of the core of the granule without a shell. For sertraline particles, the shell makes up from 15 to 200% of the mass of the core of the granule without a shell.

Salt

This invention relates to sertraline acetate, which can be obtained in accordance with the following method.

Sertraline free base is dissolved in a suitable organic solvent, such as ethyl acetate; unsaturated hydrocarbon such as hexane or pentane; an aromatic hydrocarbon such as benzene or toluene; or a cyclic or acyclic ether, such as dioxane, tetrahydrofuran, diethyl ether or methoxymethyl ether, or a combination or combination of any of these solvents with water. A suitable organic solvent is any solvent in which the sertraline free base is freely soluble, in which the sertraline acetate salt is particularly insoluble and which facilitates the formation of the desired crystalline form. Hexane is preferred due to its ability to dissolve sertraline, its inability to dissolve sertraline acetate and because of the quality of the crystals obtained by granulation in it. The temperature of the solution is maintained at room temperature or raised to the boiling point of the solvent used. It is preferable to raise the temperature to a value slightly lower than the boiling point of the solvent used, usually in the range of 30 to 60 ° C. When hexane is used, it is preferable to raise the temperature to about 40 ° C. Excess acetic acid is then added to the reaction mixture. It is usually preferred to add one or two equivalents of acetic acid for each equivalent of sertraline. Usually 1.1 equivalent of acetic acid is added. When the reaction ends, sertraline acetate usually precipitates. Sometimes, in order to obtain a better yield of said sertraline acetate, the reaction mixture is cooled, usually to about room temperature or about 0 ° C. After salt precipitation, it is usually preferable to continue mixing or granulating the precipitate. It is usually preferable to granulate at room temperature or at a temperature slightly above room temperature, but not more than 35 ° C. The resulting crystals are separated by filtration. Sertraline acetate salt crystals are washed with hexane and dried at elevated temperature and reduced pressure, usually 3060 ° C for 24 to 48 hours, or a period of time sufficient to remove substantially all traces of hexane and any unreacted acetic acid.

Alternatively, sertraline acetate can be obtained directly from a salt of sertraline, for example sertraline hydrochloride or sertraline mandelate, without isolating the sertraline free base form. Typically, sertraline hydrochloride is used in this preparation. Using this method, said sertraline salt is suspended in water and a diluted aqueous base is added dropwise or in small portions. During the addition of the base, the pH of the solution is monitored to prevent the addition of excess base. Typically, the pH is maintained between about 6.5 and 9.5. Preferably, the pH is maintained at 8.5. Suitable aqueous bases that can be used in this reaction include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. Aqueous sodium hydroxide is preferably used. The sertraline free base thus obtained is separated in an immiscible organic solvent, such as hexane, ethyl acetate, benzene, toluene or ethers, such as diethyl ether, dioxane or methoxymethyl ether. Hexane is generally preferred. The immiscible organic phase is separated from the aqueous phase, and the organic phase is washed with water to remove chloride ions. The organic phase containing the sertraline free base form is then treated as described in the previous paragraph to obtain sertraline acetate.

This invention also relates to sertraline lactate, which can be obtained in accordance with the following method.

Sertraline free base is dissolved in a suitable organic solvent, such as ethyl acetate; unsaturated hydrocarbon such as hexane or pentane; an aromatic hydrocarbon such as benzene or toluene; or a cyclic or acyclic ether, such as dioxane, tetrahydrofuran, diethyl ether or methoxymethyl ether, or a combination or combination of any of these solvents with water. A suitable organic solvent is any solvent in which the sertraline free base is freely soluble, in which the sertraline L-lactate salt is particularly insoluble and which facilitates the formation of the desired crystalline form. Ethyl acetate is preferred because of its ability to dissolve sertraline, its inability to dissolve sertraline L-lactate and because of the quality of the crystals obtained by granulation therein. The temperature of the solution is maintained at room temperature or raised to the boiling point of the solvent used. It is preferable to raise the temperature to a value slightly lower than the boiling point of the solvent used, usually in the range of 30 to 60 ° C.

When hexane is used, it is preferable to raise the temperature to about 40 ° C. Then, excess L-lactic acid is added to the reaction mixture. It is usually preferred to add one or two equivalents of lactic acid for each equivalent of sertraline. Usually 1.1 equivalent of lactic acid is added. When the reaction is complete, sertraline L-lactate usually precipitates. Sometimes, in order to obtain a better yield of sertraline L-lactate, the reaction mixture is cooled, usually to about room temperature or about 0 ° C. After salt precipitation, it is usually preferable to continue mixing or granulating the precipitate. It is usually preferable to granulate at room temperature or at a temperature slightly above room temperature, but not more than 35 ° C. The resulting crystals are separated by filtration. The crystals of the sertraline L-lactate salt are washed with ethyl acetate or hexane and dried at elevated temperature and reduced pressure, usually 30-60 ° C. for 24 to 48 hours, or a period of time sufficient to remove substantially all traces of hexane and any unreacted lactic acid .

Alternatively, sertraline L-lactate can be obtained directly from a sertraline salt, for example sertraline hydrochloride or sertraline mandelate, without isolating the sertraline free base form. Typically, sertraline hydrochloride is used in this preparation. Using this method, said sertraline salt is suspended in water and a diluted aqueous base is added dropwise or in small portions. During the addition of the base, the pH of the solution is monitored to prevent the addition of excess base. Typically, the pH is maintained between about 6.5 and 9.5. Preferably, the pH is maintained at 8.5. Suitable aqueous bases that can be used in this reaction include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. Preferably, aqueous sodium hydroxide is used. The sertraline free base thus obtained is distributed in an immiscible organic solvent, such as hexane, ethyl acetate, benzene, toluene or ethers, such as diethyl ether, dioxane or methoxymethyl ether. Hexane is generally preferred. The immiscible organic phase is separated from the aqueous phase, and the organic phase is washed with water to remove chloride ions. The organic phase containing the sertraline free base form is then treated as described in the previous paragraph to obtain sertraline Lactate.

Sertraline L-lactate can also be prepared directly from sertraline mandelate. Using this method, sertraline mandelate, which is obtained by the method described in US patent No. 4536518, suspended in a mixture of water and a suitable organic solvent. Suitable organic solvents for this reaction include ethyl acetate, unsaturated hydrocarbons such as hexane or pentane, aromatic hydrocarbons such as benzene or toluene, and cyclic or acyclic ethers such as dioxane, tetrahydrofuran, diethyl ether and methoxymethyl ether. The suspension is usually cooled to a temperature below room temperature, such as a temperature in the range of 0 to 20 ° C. Typically, the reaction mixture is cooled to approximately 1 5 ° C. Suitable bases for this reaction include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. Preferably, aqueous sodium hydroxide is used. A sufficient amount of base is added to the reaction mixture to ensure complete conversion of sertraline mandelate to the free base of sertraline. Typically, this conversion is completed when the pH of the aqueous layer is approximately 9.6. The organic layer containing sertraline free base is separated from the aqueous portion and the aqueous portion is usually extracted with additional parts of the organic solvent. The organic layers are combined and concentrated. Filtration may sometimes be necessary to clean the solution. Lactic acid is added directly to this solution, and the reaction mixture is usually stirred for an extended period to granulate the resulting sertraline Lactate. Typically, stirring is continued for 8 to 48 hours, and preferably for 16 to 24 hours. Sertraline L-lactate is then isolated and purified as described later in this invention.

The present invention also relates to sertraline L aspartate, which can be prepared according to the following process.

Sertraline free base is dissolved in a suitable organic solvent, such as ethyl acetate; unsaturated hydrocarbon such as hexane or pentane; an aromatic hydrocarbon such as benzene or toluene; or a cyclic or acyclic ether, such as dioxane, tetrahydrofuran, diethyl ether or methoxymethyl ether, or a combination or combination of any of these solvents with water. A suitable solvent is any solvent in which the free base of sertraline is freely soluble, in which the salt of aspartate sertraline is particularly insoluble and which facilitates the formation of the desired crystalline form. Ethyl acetate in combination with a small amount of water is preferred due to its ability to dissolve sertraline and L-aspartic acid, its inability to dissolve sertraline L aspartate and because of the quality of the crystals obtained by granulation therein. An ethyl acetate solution containing two to three percent water is preferably used. An ethyl acetate solution containing three percent water is especially preferred. The temperature of the solution is maintained at room temperature or raised to the boiling point of the solvent used. It is preferable to maintain the temperature at room temperature. Then, an excess of aspartic acid is added to the reaction mixture. It is usually preferable to add one or two equivalents of aspartic acid for each equivalent of sertraline. Usually 1.1 equivalent of aspartic acid is added. When the reaction is complete, sertraline aspartate usually precipitates. Sometimes, in order to obtain a better yield of sertraline L-aspartate, the reaction mixture is cooled, usually to about room temperature or about 0 ° C. After salt precipitation, it is usually preferable to continue mixing or granulating the precipitate. It is usually preferable to granulate at room temperature or at a temperature slightly above room temperature, but not more than 35 ° C. The resulting crystals are separated by filtration. The crystals of the sertraline L-aspartate salt are washed with ethyl acetate or hexane and dried at elevated temperature and reduced pressure, usually 30-60 ° C. for 24 to 48 hours, or a period of time sufficient to remove substantially all traces of hexane and any unreacted aspartic acid .

Alternatively, sertraline L-aspartate can be prepared directly from a salt of sertraline, for example sertraline hydrochloride or sertraline mandelate, without isolating the sertraline free base form. Typically, sertraline hydrochloride is used in this preparation. Using this method, said sertraline salt is suspended in water and a diluted aqueous base is added dropwise or in small portions. During the addition of the base, the pH of the solution is monitored to prevent the addition of excess base. Typically, the pH is maintained between about 6.5 and 9.5. Preferably, the pH is maintained at 8.5. Suitable aqueous bases that can be used in this reaction include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. Diluted sodium hydroxide is preferably used. Free. the sertraline base thus obtained is distributed in an immiscible organic solvent such as hexane, ethyl acetate, benzene, toluene or ethers such as diethyl ether, dioxane or methoxymethyl ether. Two to three percent aqueous ethyl acetate is generally preferred. The immiscible organic phase is separated from the aqueous phase, and the organic phase is washed with water to remove chloride ions. The organic phase containing the sertraline free base form is then treated as described in the previous paragraph to obtain sertraline L-aspartate.

Sertraline free base is prepared as described in US Pat. No. 4,536518, or by neutralizing an aqueous solution of a salt of sertraline, such as, for example, sertraline hydrochloride or mandelate of sertraline together with an aqueous base, such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate . Sertraline free base may be used in solution or may be isolated as a crystalline solid.

Sertraline hydrochloride and sertraline mandelate are prepared by methods described in US No. 4536518.

The hygroscopicities of sertraline acetate, sertraline lactate and sertraline aspartate are measured using microbalance for determining moisture, such as microbalance for determining moisture νΤΙ (microbalance for determining moisture νΤΙ. MV 3006 and MV 300 ^. ΝΤΙ Sogrogayop, H1a1eay. Popba, USA). Sertraline acetate, sertraline L-lactate and sertraline acetate are exposed in an atmosphere having a humidity range of 10 to 90%. A temperature of 25 ° C is maintained during all changes in hygroscopicity. Moisture adsorption and desorption isotherms for sertraline acetate, sertraline L-lactate and sertraline aspartate in these atmospheres are determined using microbalances to determine the moisture νΤΙ. Sertraline acetate, sertraline L-lactate and sertraline aspartate are not hygroscopic within the limits of the studied humidity.

The mechanical properties of sertraline acetate and sertraline L-lactate are determined by testing the pressing pressure, solid fraction, dynamic indentation, reduced elastic modulus, quasistatic indentation, shear modulus and their tensile strength. Tab. 1 presents the results of testing the mechanical properties of sertraline acetate.

Table 1. Mechanical properties of sertraline acetate

Property Test Sertraline Acetate Pressing Pressure, MPa Tight preparation laziness 36.7 (2.5) Solid fraction Tight preparation laziness 0.831

Dynamic indentation hard., MPa Dynamic indentation 60.0 (0.4) Reduced modulus of elasticity, GPa Dynamic indentation 5.1 (0.5) Quasistatic indentation hard., MPa Quasistatic indentation 25.1 (1.3) Elastic modulus, GPa Quasistatic indentation 2.2 (0.2) Shear modulus, GPa Quasistatic indentation 99.9 (19.1) Tensile Strength, MPa Tensile fracture 0.52 (0.03)

Tab. 1a presents the results of testing the mechanical properties of sertraline L-lactate

Table 1a. Mechanical properties of sertraline L-lactate

The properties Test Sertraline b-lactate Pressing Pressure, MPa Tight preparation laziness 52.8 (0.7) Solid fraction Tight preparation laziness 0.862 Dynamic indentation hard., MPa Dynamic indentation 81.6 (1.6) Reduced modulus of elasticity, GPa Dynamic indentation 7.4 (0.6) Quasistatic indentation hard., MPa Quasistatic indentation 31.1 (1.4) Elastic modulus, GPa Quasistatic indentation 2.0 (0.2) Shear modulus, GPa Quasistatic indentation 113.9 (4.6) Tensile Strength, MPa Tensile fracture 0.56 (0.02)

Mechanical properties such as tensile strength, elastic modulus and hardness of pharmaceutical pressed powder blanks (drugs, excipients, as well as drugs and excipients) cannot be evaluated by standard methods used in metallurgy, since pharmaceutical solids cannot be pressed into homogeneous fully dense body. In general, the following four categories of mechanical properties are evaluated regularly: elasticity, viscoelasticity, ductility, and kink. All four categories correspond to three events of the pressing method, i.e. pressing, curing and reducing compression. Assessing the mechanical properties of pharmaceutical powders is complex because important parameters that affect the measurement of mechanical properties, such as particle size distribution, crystal habit, surface texture, crystallization degree, and crystallographic symmetry are significantly different for these substances. However, tabletting performance (hereinafter referred to as PIT) is used to predict the tabletting performance of pharmaceutical pressed powder blanks (Sheyapb Ε.Ν .. διηίΐΐι

I.R. Ro \\ 'bsg Theseus., 38: 145-159, 1984; Sheyapb Ε.Ν., 8th Ό.Ρ. Αάν. Segat., 9: 47-57, 1984). These indicators are derivatives of important measurements made to determine the mechanical reaction of pressed powder blanks (measurements are not performed during the pressing process). By measuring and calculating these mechanical properties, one skilled in the art can understand the fundamental properties of a pharmaceutical powder. This understanding allows a specialist to determine whether a dosage form can be manufactured. The measurement and calculation of the mechanical properties of PPTs, such as tensile strength, indentation modulus, and hardness of a pressed powder billet, were carried out in accordance with the methods described by Eyapb (I. Ryagt. 8sk, 60: 758-763, 1971; I. Ryagt. 8c1 ., 63: 605-612, 1974; I. Ryagt. 8sk, 74: 768770, 1985; Ryagtaseysa Tesipodu, 8: 54-66, 1989; Ιηΐ. I. Ryagt., 67: 217-229, 1991; Ιηΐ. I. Ryagt., 67: 231-246, 1991).

Measurements of mechanical properties can be regularly performed using square pressed powder blanks from a pure drug substance, in this case sertraline acetate and sertraline L-lactate. The measurements are carried out three times and the pressed powder billets are prepared by pressing along one axis and reducing compression along three axes.

The most important properties of a substance that affect the compaction of a powder are its viscosity, elasticity and tensile strength. Viscosity is determined by pendulum impact and dynamic indentation test to determine the hardness of the pressed powder billet. The hardness of a compound is inversely related to its viscosity. Since plastic deformation enhances the bonding between particles, high viscosity and low hardness are most desirable. Typically, dynamic indentation hardness values below 100 MPa are high, values in the range of 100,200 MPa are acceptable, and values greater than 200 MPa are low.

The modulus of elasticity (also known as Young's modulus (Wonnd)) of the pressed powder billet is determined by measuring the amount of pothole recovery after a lengthy test to determine the (quasielastic) indentation hardness. It is desirable that the substance has a low elasticity response while reducing compression, which suggests that the substance should exhibit a low modulus of elasticity. Elasticities greater than 8 GPa are high, values between 1-8 GPa are average, and values below 1 GPa are low.

The tensile strength is measured by transverse pressing of pressed powder blanks before it results in a fracture in tension. It is desirable to have a high tensile strength. A tensile strength greater than 2 MPa is high, values ranging from 0.8 to 2.0 MPa are moderate, and values less than 0.8 MPa are low.

The Hestand's PEP (Sheaaaa) consists of the following characteristics: cold-brittle fracture index (hereinafter referred to as the ICH), a binding index at best (hereinafter referred to as LIS), a binding index at worst (hereinafter referred to as ICX) ), and the strain index (hereinafter referred to as ID).

ICI is the tendency of a pressed powder billet to break or fragment under pressure from existing fractures and openings in a pressed powder billet. ICI is used by specialists to indicate the tendency of a pressed powder preform to break or fragment during processing (i.e. failure), such as during removal from a tablet press or during film coating. A cold break index of 0 is excellent, values ranging from 0.01 to 0.09 are good; values ranging from 0.1 to 0.19 are valid and values ranging from 0.2 to 1.0 are bad.

The binding index is evaluated by the ability of the pressed powder preform to maintain bonds between particles during elastic deformation. Hestand believed that the process of plastic deformation is the main mechanism for the formation of bonds in the tablet, when the pharmaceutical powder is subjected to pressure during loading. The plastic strain estimate is used in calculating the binding index. Evaluation of the binding index is important, since reducing compression is an important step in the manufacture of tablets. The worst-case binding index (ISL) and the best-case binding index (LIS) determine the ability of the bonds between particles that formed during compression to be maintained during release of tensile energy during compression. In conditions of high speed of manufacture of tablets ISX is more applicable than LIS. Binding index values greater than or equal to 2 are excellent; values ranging from 0.8 to 1.9 are good; values ranging from 0.3 to 0.7 are acceptable and values less than 0.3 are bad.

The strain index is a measurement of the elastic deformation of a pressed powder billet. It can also be defined as measuring elastic strain during the unloading phase. Elastic deformation from the indentation method can be used to evaluate the elastic modulus.

Samples for testing mechanical properties are prepared in accordance with standard methods. To obtain reliable data, these samples must be free of mechanical defects, such as microcracks. Therefore, a specialized tablet press was used, prepared as described in US Pat. No. 4,880,373. This press compresses the powder in one axis (i.e., in one dimension) and then slowly reduces the compression of the powder in three axes (i.e. in three dimensions). Samples are pressed with a predetermined degree of compression, called the standard state. The standard pressing method is the pressing of powders to a solid fraction of 0.85. The solid fraction, or relatively dense, is the apparent density of the pressed powder billet divided by the actual (absolute) density of the pressed powder billet. The apparent density of the pressed powder billet is determined by measuring its volume and dividing by mass. This measurement is usually carried out in cubic centimeters per gram. The actual density of the pressed powder billet is determined by gel pycnometry. Usually, to achieve the desired solid fraction, control pressings of carefully weighed powder samples should be carried out, and the solid fraction of the obtained pressed powder billet should be measured. Correction of the solid fraction is achieved by increasing or decreasing the mass of the powder.

Square pressed powder blanks that serve as test samples are prepared using a three-axis compression compression tablet press prepared as described in US Pat. No. 4,880,373, with a square composite matrix and 1.9 cm upper and lower square punches. Preliminary the lubricated matrix and the lower punch are installed in a tablet press and the matrix is filled with pre-weighed powder. The surface of the powder is smoothed with a spatula and the upper punch is placed in a matrix on the surface of the powder. To ensure a high level of accuracy, the method is usually computerized. The hydraulic ejector matrix is brought into a state of full extension, pressing the halves of the matrix tightly to each other. Then, the pusher ejector is brought into a state of complete elongation by pressing the powder along one axis. When the jack reaches full elongation, it is left in this state for a holding period of 5 minutes. During this holding, the forces of the punch and die are weakened due to the weakening of pressure in the sample. By the end of aging, the computer removes the forces of the metal on the metal of the hydraulic cylinders of the punch and the matrix and then begins to reduce compression along three axes for 15 minutes During this phase, the forces of the punch and die are simultaneously removed, maintaining pressures at the level of 1 to 1, until the minimum forces achieved by the hydraulic system are reached. The obtained pressed powder billet is then removed and the process repeated. Pressed powder blanks with a central hole are prepared in the same manner, except that the lower punch carries a spike with an inserted spring mounted in the punch. Typically, the central hole passes through 75% of the pressed powder billet. A press with a micro-drill corresponding to almost the same diameter as the punch spike is used to complete the hole. All samples are left alone for an 18 to 24 hour period before testing.

Pressed powder billets after a period of rest are used as test specimens for mechanical measurements. The following table shows the test methods, key measurements, and properties identified by the tests.

Table 2. Methods of testing mechanical properties and measurements

Way Key Measurements Measured Properties Derived Properties Indentation hardness 1 Starting height, 11, 2 Rebound height, 11, 3 Chord radius, and Dynamic hardness, N _about 1 Reduced elastic modulus, Y '2 Viscoelastic constant, CV 3 Worst binding index, IP _X 4 Cold brittleness / viscoelastic binding index, xISv Indentation hardness 1 Weakened force, P 2 Chord radius, and 1 Quasistatic hardness, N ₁₀ 2 Shear modulus, O 1 Binding index at best, IP _l 2 Viscoelastic constant, CV 3 Elastic modulus, Y ' Kink 1 Strength, P 2 Thickness of pressed powder billets, T 1 Tensile strength, σ-t 1 Worst binding index, IS _X 2 At best binding index, ISL 3 Cold brittle fracture index, II 4 Cold brittle / viscoelastic binding index, xISv Kink 1 Strength, P 2 Thickness of pressed powder billets, T 1 Accepted tensile strength, Oto 1 Cold-brittle fracture index, II Powder fluidity 1 Shear strength 1 Effective angle of internal friction 1 Single Yield Index, YPC

The dynamic indentation hardness H _{o of the} pressed powder billet is measured in a pendulum-impact apparatus prepared as described in US Pat. No. 4,885933. The pressed powder billet is placed in air-operated clamps with a solid liner behind the pressed powder billet. The spherical pendulum has a known mass and diameter and is mounted with a predetermined initial angle before release. The pendulum is released in the direction of the pressed powder billet, it hits the pressed powder billet and bounces. The time required for the pendulum to pass between two photographic plates spaced a predetermined distance and the height of the bounce of the pendulum is measured, 11 _{g are} automatically calculated. These measurements and calculations are usually made by a computer. The pressed pressed powder billet is removed from the clamps and placed on the surface of the profilometer (8igTapa1ukheg 5000, Eeebega Przobysch 1ps., Prgoupseps, Vnobe Spap). The probe is carefully installed in a certain position, and then it moves along the surface of the dent, crossing it. Three parallel scans are performed on each dent. The first is carried out through the center of the dent and the second and third are carried out at an equal distance on the same side as the first scan. The data of the indicators of all three scans are stored and analyzed by measuring in a circular curve to determine the radius of the chord of dents for calculating H _about in accordance with equation (1),

But = ((4tdgy _r ) / pa ⁴ ) * ((B / _r ) -0.375) (1), where r and r represent the mass and radius of the squeezer, q represents the constant of attraction, and represents the radius along the dent chord and N and N _g represent the initial height and height of the rebound of the indenter.

The quasistatic indentation hardness H10 is determined by the slow indentation of a spherical indenter driven by an engine, prepared as described in US Pat. No. 4,957,003, into the surface of the pressed powder billet for a predetermined distance and holding it in this position for a fixed period of time. This determines the holding period. Typically, the indenter is held in this position for about five to twenty minutes, preferably for ten minutes. At the end of the retention period, the force of the indenter is repeated. The pressed powder billet is removed, its dent is carefully examined and analyzed as described above for the pendulum test and H _{10 is} calculated in accordance with equation (2),

But = E _g / (pa ² ) (2), where E _g represents the weakened force of the indenter after the holding period, and a represents the radius of the dent along the chord. The pressed powder billet is held in place by pneumatic driven clamps. The diameter of the indenter is the same as the diameter of the pendulum (2.54 cm). The penetration depth of the quasistatic indenter is such that the radius of the dent in the chord will correspond to the radius obtained in the impact test.

The tensile strength of normal pressed powder billets, and _t is determined by transverse pressing of the pressed powder billet until it breaks between the fixed plate and the motor driven plate of a given width. The force on the plates is continuously monitored, and indicators of the dependence of force on time are displayed on the computer screen after the test. The indicators are analyzed by identifying a break point, which usually represents a sharp decrease in strength. An event marker is also used to help identify the fault when the sample is noticeably destroyed. The tensile strength is then calculated in accordance with equation (3), στ = Razlom _a / (^ p * T) * PTE (3), where \ ¥ _p is the width of the plate, T is the thickness of the pressed powder billet, and PTE represents the perpendicular tensile force, which is 0.16 when the plate width is 40% of the width of the pressed powder billet. The level of pressing in the test is controlled by calculating the time constant and adjusting the speed of the plate so that the time constant is in the interval between ten and twenty seconds. With equal time constants, the effect of viscoelasticity of the substance is avoided. Time constant defined as the time, expressed in seconds, at rates of force versus time finding ^{schihsya between} Erazloma ^and E |.) N ;; 1oma ^{/ e} · ^{E where} fracture ^{representable} a force at which the compact breaks and Erazloma / e is an exponent. The time difference between Erazloma and Erasloma / e is defined as a time constant. Normalization of the time constant is included in the calculations to eliminate the contributions of the viscoelasticity of the substance with respect to its fracture.

The accepted tensile strength, σ., „Is measured on pressed powder blanks with a central hole, using the same apparatus and engine speed settings as a normal test of tensile strength. It is calculated in accordance with equation (3) above.

Evaluation of the fluidity of the powder is carried out using a simplified plate-type shear cell on non-pressed powders after they are balanced for at least 18 hours to a predetermined relative humidity (RH), typically 50% at ambient temperature. Shear cells are prepared as described in Sheyapi and ^ 11soh,

I. Ryagt. Bsk, 1969, 58, 1403-10; Sheyapy et al., I. Ryagt. Bsk, 1973, 62, 1513-1517; and H1e§1apy and ^ e11§, Prgosey1n§5 I p! eqpa (1op1 Po \\ yeg apy Vi1k Boyyk Napypd apy Prgosekpd SopGegepse, VoketpoSh, 1b, May 10-12 (1977). Rotating powder layer, from 4 to 6 mm of thickness and from 63.5 to 82.5 mm in diameter, formed on coarse sandpaper using a matrix, the matrix is removed and the slide, which is attached to the input cell using a towing line, is placed on powder. The load is placed on the slide and the engine is started a machine that pulls a weighted slide through the powder. The drag force is continuously measured by input cell, the force increases rapidly to the maximum before the slide begins to move through the powder with a shear movement, and a decrease in force is observed. The direction of the engine is then reversed until the towing thread is weakened. The engine is then pulled again to maximum force and the direction of the engine is reversed. The process is repeated several times before maximum power is reproducible.

The powder layer is then restored to its previous form. A slide carrying an identical load is returned back to the top of the powder. The foregoing process is repeated until a lack of increase in strength is obtained. The powder layer is straightened and the whole process is repeated with various weights on the sled. The effective angle of internal friction is calculated as the arc tangent of the slope of the plot of shear stress versus seal stress. This parameter is used to calculate the Single Yield Index, YPC, as shown in equation (4),

EPK = 0.667 * (42-σ) (4), where σ is the effective angle of internal friction.

Sertraline acetate does not have any drawbacks that prevent the formation and maintenance of bonds between particles during compression and compression reduction. In particular, sertraline acetate has exceptional mechanical properties and particle binding ability, and is thus an excellent candidate for tablet production.

The values of the internal mechanical properties of the lactate salt indicate that it does not have brittleness, which can impede the formation and maintenance of particle bonding during compression and reduction of compression.

It was found that the tensile strength of sertraline L-lactate is very high. Also, the pressure during compression of the salt of sertraline lactate is greater than its hardness. Values for sertraline lactate salt indexing indices indicate that it is an excellent candidate for tablet manufacture. In general, sertraline L-lactate has exceptional mechanical properties, the ability to bind particles, and tableting index values. Thus, sertraline L-lactate is an excellent candidate for the manufacture of tablets.

The crystallinity of sertraline acetate, sertraline Lactate, and sertraline L-aspartate is determined by polarized light microscopy and X-ray powder diffraction. The powder X-ray diffraction pattern is determined at ambient temperature using an X-ray diffractometer (0 | GGgak1ote1eg 5000. B1etep§ Lpa1uysa X-Gau Buietk, 1ps., 6300 Egrgie Lape, Maikop, XVI 53719-1173). Typically, the samples are placed in an aluminum holder and examined at a diffraction angle of 2θ, increasing from 5 to 35 °, with a step size of 0.02 ° and a counting time of one second. Temperature characteristics, melting point, heat of fusion, and mass loss during heating are determined using two instruments: a differential scanning calorimeter (EBS 4, Regksh E1teg, USA) and a thermogravimetric analyzer (BBS 5200, Be1ko, 1arap).

To determine the solubility of sertraline acetate, sertraline b-lactate and sertraline b-aspartate, an aliquot of sertraline acetate, sertraline b-lactate and sertraline b-aspartate is added to a measured amount of water in a screw cap tube. To speed up the achievement of equilibrium, a saturated solution can be prepared at a temperature higher than the ambient temperature. The tube is placed on a rotator, which is immersed in a water bath at 40 ° C. At this temperature, a sufficient amount of sertraline salt is added to the excess solids in vitro. The tube is maintained at 40 ° C for 6 hours, during which the temperature decreases to 15 ° C for two hours. The temperature of the tube is then brought to 25 ° C and maintained at this temperature for up to two days. At the end of the equilibration time, the solution was filtered, the pH of the filtrate was measured, and an aliquot of the filtrate was analyzed by HPLC to determine the concentration of sertraline in the solution. HPLC analysis was carried out using a column \ νη ^ Γ5 Butteuu S-18, 250 x 4.6 mm, the elution rate of the solution of the mobile phase 1 ml / min The column can be purchased from ΧνηΚΓδ Sogr., 34 Mar1e B1gee (MiGogy, MA 01757. A solution of the mobile phase is prepared by mixing 270 ml of tetrahydrofuran, 230 ml of meta81 nol and 400 ml of buffer. The buffer is prepared by adding 1.7 ml of phosphoric acid and 3, 5 ml of triethylamine per liter of water. The excess solids in the tube are collected, dried and then crystallinity is examined using microscopy and temperature analysis. The instant salt of the acetate of this invention has a solubility of 84 mg / ml in water. The instant L-lactate salt of this invention has a solubility in water of 125 mg / ml The instant aspartate salt of this invention has a solubility in water of 28.6 mgA / ml.This high degree of solubility in water allows more sertraline to be released over a shorter period of time, which is especially suitable for acute symptoms In addition, high solubility is favorable in oral controlled release osmotic dosage forms that release a sertraline solution in a controlled manner.

The chemical resistances of sertraline acetate, sertraline L-lactate and sertraline b-aspartate are determined using reverse-phase HPLC analysis (reverse phase HPLC, the same conditions as above) of samples that are tested for increased stability. In an increased stability test, sertraline acetate samples are subjected to various combinations of humidity and temperature conditions over varying lengths of time. The following combinations of humidity and temperature are particularly suitable for evaluating the chemical stability of sertraline and various forms of its salts. In these studies, the activity of sertraline acetate and the presence of impurities and degradation products are quantified. It is generally believed that a drug is stable if the amount of detected new impurities is less than 0.1% of the amount of drug used. Determine the stability of sertraline acetate, sertraline L-lactate and sertraline aspartate in the solid state, as well as in solution.

Testing increased resistance carried by the fact that subjected acetate, sertraline L-lactate, sertraline or aspartat sertraline standard test conditions of temperature and humidity as defined by the principles 1SN (1p1egpayopa1 SopGegepse og ΗαηηοηίζαΙίοη Og Tes1pysa1 es |. Shgetep15 Gogh Chez Ved151gayop Og RyagtaseiysaI Gogh Nitap Ike) . Typically, a sample of sertraline acetate, sertraline L-lactate or sertraline L-aspartate is evaluated at 40 ° C ± 2 ° C / 75% relative humidity ± 5% over a period of 24 weeks. In addition, samples are placed under the following conditions: 50 ° C ± 2 ° C / 20% relative humidity over a period of 24 weeks; 70 ° C ± 2 ° C / relative humidity <10% for a period of 3 weeks. The stability of sertraline acetate, sertraline L-lactate or sertraline L-aspartate is also evaluated by placing them in 0.01n. hydrochloric acid solution for 6 weeks at 50 ° C and in 0.01n. sodium hydroxide solution for 6 weeks at 50 ° C. In all samples subjected to stability testing, purity and degradation were assessed by performing reverse phase HPLC analysis using the same conditions as described above. When the above experiments are performed on sertraline acetate, sertraline L-lactate or sertraline aspartate, no new degradation products are observed at levels greater than 0.1% of the parent compound. The purity of each of the samples of sertraline acetate, sertraline L-lactate and sertraline L-aspartate is more than 99%.

In the treatment of the diseases and conditions described in this invention and claimed in the attached claims, sertraline acetate, sertraline L-lactate or sertraline b-aspartate can be obtained in the form of immediate release dosage forms as described, for example, in US patent No. 4536518. Alternatively, sertraline acetate, sertraline L-lactate or sertraline L-aspartate can be prepared in a controlled release dosage form, such as a sustained release dosage form Single form or encapsulated solution dosage form with delayed release. A method for preparing and using such sustained release formulations with an encapsulated solution and sustained release is described in the United States Assignment, which is undergoing simultaneous review, under the title of Lepryoptera erythrocyte erythromycin, and Peaueb-Beehepti ebie PC9838TP and PC9824TL numbers, respectively, each of which is a PCT application pointing to the United States, and each of which is incorporated into this invention by reference and.

In general, sertraline acetate, sertraline L-lactate and sertraline L-aspartate are typically administered in doses ranging from about 0.2 mgA / kg body weight per day to about 10 mgA / kg body weight per day, although variations are unavoidable will arise depending on the condition of the subjects being treated, and the particular route of administration chosen. Typically, a preferred dose range is from about 15 mgA of sertraline acetate, L-sertraline L or aspartate sertraline per day to about 200 mgA of sertraline acetate, L-sertraline L or sertraline L-aspartate per day for an average adult subject having a body weight of about 70 kg . However, the preferred dose amount will depend on the dosage form in which sertraline acetate, sertraline L-lactate or sertraline b-aspartate is administered, as well as other factors that will be readily apparent to those skilled in the art, such as the attending physician.

The abbreviation MPa used in this invention is megapascals and the abbreviation GPa is gigapascals.

As used herein, the term osmotic tablets defines a controlled release solid dosage form driven by osmotic pressure.

For convenience and consistency, reference to sertraline in terms of therapeutic amounts or rates of release in the claims refers to active sertraline, abbreviated herein as mgA, i.e. to sertraline, which is not a salt, which is an unhydrated free base having a molecular weight of 306.2 g / mol. Amounts expressed in mgA can conveniently be converted into equivalent masses of sertraline acetate, which has a molecular weight of 366.3 g / mol. The molecular weight of the form of sertraline acetate · 1/4 hydrate is 370.8 g / mol. The molecular weight of sertraline L-lactate is 396.3 g / mol. The molecular weight of sertraline L-aspartate is 439.3 g / mol.

The invention will be illustrated by the following examples, to which it is not limited. In general, the examples demonstrate the frequency of gastrointestinal side effects with oral administration and intravenous administration of sertraline, a decrease in the severity of these side effects by taking controlled-release doses, and the preparation of dosage forms for the sustained release of sertraline within the scope of this invention, salts, methods for their preparation etc.

The following examples use the following definitions and tests:

1. C is used to indicate the amount of sertraline either in mgA or in percent (%), as indicated. O is associated with the time or time of selection, at which the indicated aliquot of the solution is taken for analysis of sertraline, the time of selection or the time of selection is indicated in hours as a subscript. Thus, p ₁ , constituting 15%, means that 15% of the dose of sertraline dissolves within 1 h.

2. Determination of the amount in percent (%) means the percentage by weight based on the total weight, unless otherwise indicated.

3. ί ₈₀ % means the time, in hours, at which 80% of the dose of sertraline is released from the dosage form.

4. The release rate was determined in accordance with the following equation: the release rate is 0.8 * (dose) / ΐ _80% or ₂₄ C / 24 if 80% of the sertraline is not released within 24 hours.

5. §ige1ea8e® is a registered trademark of ί’οίοΐΐοη 1pc, ’no. RA for aqueous fully plasticized polymer dispersion of ethyl cellulose.

6. Orabtu® is a registered trademark of п’οίοΐΐοη 1pp., ’No. ΓοιηΙ, RA for the plasticized cellulose ethers family, which include hydroxypropyl methyl cellulose, hydroxypropyl cellulose and methyl cellulose, which are used as powders for reconstitution in water.

7. mgA is the abbreviation for milligrams of active sertraline. For example, 200 mgA refers to 200 mg of active sertraline.

8. X mgA of a plurality of particles (where X is a number) denotes a mass of a plurality of particles containing X mgA. For example, 100 mgA of a plurality of particles refers to a mass of a plurality of particles containing 100 mg of active sertraline.

9. ίη νίίτο Dissolution Test: The following ίη νίίτο test can be used to test the sustained release embodiments of the present invention for ίη νίνο stability. If a particular dosage form meets the ίη νίίτο criterion or the ίη νίνο criterion. described in this invention, it is within the scope of this invention.

Dosage forms with prolonged release of sertraline are tested in a standard И8Р apparatus with rotating blades, as described in Fig. 81-1E5 Ria ^ tacore ^ a XXIII (I8R) Ωίδδοίυΐίοη TechC11ar1eg 711, Arragac | 5 2. The blades rotate at a speed of 50 rpm rpm if the dosage form is many particles or quickly breaks up into many particles) and the dissolution is carried out in, as a test medium, 900 ml of acetate buffer (0.13 M acetic acid) with 0.075 M sodium chloride, using potassium hydroxide for order to bring the pH to 4 , 0 at 37 ° C. Dissolution vessels are closed to prevent evaporation. If gelatin capsules are used, then 0.1 mg / ml trypsin enzyme should be added to the buffer. At indicated times after the start of the test (i.e. immersion of the dosage form in the apparatus), filtered aliquots of the test medium (typically 2 or 10 ml) are collected and analyzed for sertraline using high performance reverse phase liquid chromatography (HPLC) or another suitable method quantitative analysis. Dissolution results are presented in the form of time-dependent dissolved sertraline in mgA or the time-dependent percentage of dissolved active sertraline. Sustained release dosage forms that satisfy the following criteria are within the scope of this invention: during the initial period during which 80% of the administered drug is released (1) the rate of release of sertraline is from 1 to 40 mgA / h, as described above; and (2) the rate of release of sertraline cannot exceed 40 mgA / h for any period of one hour; and (3) less than 70% of the enclosed sertraline is released within the first hour into the environment in which the use is made.

For a sustained-release embodiment followed by a sustained release, in which the retardation is a time dilation, the same test is used as described immediately above for sustained-release embodiments only, without any modifications. The dosage form will release sertraline at a rate of less than 1 mgA / h for a period of up to three hours or less, corresponding to a slowdown period, followed by a sustained release of sertraline at a rate of from 1 to 40 mgA / h.

A convenient test for embodiment with spatial slowdown followed by prolonged release of the present invention is a modified version of the two-stage test ίη νίίΓΟ for dissolution, which is described in 1995 and 8. RIagtasore1a (u8P 23), 8esuyp [724], Zykesyop Oslauzb Be1eake (Ep1eps-soa1eb) Lgis1e5-6epega1 Otid Beleeak 81apbagb. which encompasses a two-hour test for the release of sertraline in a simulated gastric fluid (acid test), followed by a test for the release of a drug in a simulated intestinal fluid (neutral test). For tablets and capsules that do not contain many particles or do not quickly disintegrate into many particles, mixing is carried out using blades rotating at 50 rpm. For sets of particles or dosage forms that break up into sets of particles, agitation is carried out using blades rotating at 100 rpm. If gelatin capsules are used, then 0.1 mg / ml trypsin enzyme should be added to the buffer. This two-stage test ίη νίΐτο can be adjusted in such a way that it is suitable for evaluating spatial slowdown embodiments of the present invention, as currently described.

For embodiments with spatial retardation followed by prolonged release, initiated by pH, the test ίη νίΐτο is carried out as described in i8P En1eps Tech! with the requirements that the dosage forms of this invention (a) release sertraline at a rate not exceeding 1 mgA / h for at least one hour in the acid phase of the test (in 0.1N HCl), and (b) sertraline was released at a rate ranging from 1 to 40 mgA / h in the neutral phase of the test, ensuring that the dosage forms release no more than an additional 70% of the sertraline contained therein during the first hour of the neutral phase of the test. If desired, the acidic portion of the dough can be carried out for more than one hour, i.e., even under more stringent conditions, and such embodiments are also within the scope of this invention. The calculation of the rate of release of sertraline during the neutral phase of this test is as follows. The speed is calculated by noting the time after deceleration for 1 h, during which an additional 80% of the dose is released into a neutral (pH 6.8) medium, then a division is made in which the numerator is 80% of the dose, expressed in mgA, and the denominator represents This is the time during which 80% of the dose is released into a neutral environment minus 1 hour (or another period of time if the acid phase is longer than 1 hour). The acidic part of the test is carried out in 750 ml of 0.1N. HC1 for 1 h. After 1 h, 250 ml of 0.2 M trisodium phosphate containing 10 g of polysorbate-80 are added to the acidic medium (containing the dosage form), and the pH is adjusted to pH 6.8 using either 2M hydrochloric acid or 2M sodium hydroxide. The solubility of sertraline is low in phosphate buffer in the second stage (pH 6.8). Thus, polysorbate-80 (1% w / v) is added to a neutral (pH 6.8) phosphate medium to increase the solubility of sertraline to provide immersion conditions for dissolution.

For embodiments with a spatial slowdown followed by a sustained release initiated by the enzymes described herein, the release of sertraline is initiated by the presence of pancreatic lipase, esterase, or protease in the small intestine. To evaluate ίη νίΐτο sustained release dosage forms followed by a sustained release of lipases, a lipase such as 5 mg / ml porcine pancreatic lipase (81dta CI. For sustained release systems initiated by an esterase or protease, suitable esterases or proteases (e.g., pancreatic esterase, trypsin, chymotrypsin, elastase) are included in the second step of the ίη νίΐτο test. Thus, the test is carried out in the same manner as for forms with spatial retardation initiated by pH, but the neutral phase is carried out in the presence of an enzyme suitable for initiating the onset of prolonged release. If esterase, proterase or lipase is denatured with polysorbate-80, then the first hour of the neutral phase is carried out in the presence of an enzyme and in the absence of polysorbate-80. After 1 h, 10 g of polysorbate-80 are added to the neutral phase.

Example 1. This example demonstrates that taking sertraline as a sustained release dosage form (200 mg dose in sixteen 12.5 mg doses given at time zero and every hour for 15 hours) results in a decrease in severity side effects compared with a single loading dose of 200 mg.

In a double-blind, randomized trial with a parallel placebo control group, healthy men were divided into three groups. Group A, called the loading dose group, received a single dose of 200 mg of sertraline in the form of two tablets of sertraline with immediate release of 100 mg (ΖΟΕΟΡΤ®). The tablets were washed down with 50 ml of water. The loading dose group also received 50 ml of a placebo solution every hour for 15 hours. The placebo solution contained lactose, menthol and polyvinylpyrrolidone to simulate the appearance and feeling of sertraline solution in the mouth, in order to guarantee blindness of the study. Group B, also called the fractional dose group, received the same total dose administered as a solution of 12.5 mg of sertraline in 50 ml of water with a frequency of one dose of 12.5 mg every hour for 15 hours. Group B also received two placebo tablets at the first dose. Group B, also called the placebo group, received placebo tablets and placebo solutions at appropriate appropriate time points. All subjects took tablets after night fasting.

Blood samples were taken before taking the medicine and at times 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 240 hours after taking the medicine. Plasma sertraline concentrations were determined using capillary gas chromatography. The total systemic effect of sertraline was determined by measuring the area under the curve of the concentration of sertraline in plasma versus time (PPC) for each subject in this group and then calculating the average PPC for this group. C _max represents the maximum observed plasma sertraline concentration achieved in a subject. T _max is the time in which C _max is reached. The pharmacokinetic data in plasma for this example are presented in table 1-1.

Before taking the medicine and at each time a blood sample was taken, each subject filled out a questionnaire, which consisted of a series of visual analogue scales with divisions, in which the subject had to assess on a scale of 010 the severity of some possible side effects. Subjects were instructed that 0 indicates no action and 10 indicates the strongest possible action.

A total of 45 subjects completed this study: 15 in each of groups A, B, and C. For eight side effects evaluated at 30 time points, a total of 10,800 ratings were obtained on individual visual analogue divisions.

Tab. 1-1 demonstrates that the total systemic effect of sertraline for the two groups taking the drug, groups A and B, as reflected in the AUC, was similar. For the fractional dose group, C _max was lower and T _max was longer than expected since the drug was taken for 15 hours rather than a single loading dose. Three subjects in the 200 mg single dose vomited at 4.25, 11.2, and 7.6 hours. Since vomiting occurred after significant plasma concentrations were reached, all three subjects and after as T _max were achieved in two, data for these subjects were not processed separately from data for other subjects. Subjects who took the medicine according to the fractional dose schedule for 15 hours did not experience vomiting. Thus, the fractional dose regimen for 15 hours exhibits a reduced vomiting frequency compared to the shock dose regimen.

Data analysis for side effects on a visual analogue scale was performed as follows.

For a specific side effect (for example, abdominal pain) in a particular subject, the effects of visual analogue scores over a period of 24 hours were summarized to give a total score. Total scores for all members of the exposed group were summarized and divided by the number of subjects in the group to obtain an average total score. The scale of this average total score did not correspond to the initial scale of 0-10, since it reflects the summation of nonzero ratings over the entire evaluation period. Tab. 1-2 represents average summary scores for a series of gastrointestinal side effects: abdominal pain, nausea, immediate bowel movements, belching, diarrhea, and abdominal cramps. Non-gastrointestinal side effects of dizziness and tremor were also evaluated.

Tab. 1-2 shows that the overall severity of side effects induced by sertraline was lower when exposed to a fractional dose for 15 hours.

Table 1-1. Sertraline pharmacokinetics for a dose of 200 mg taken as a single dose or as sixteen doses of 12.5 mg every hour for 15 hours (average values)

Impact ^C max (ng / ml) Tmax (h) ^PPK 0 ^- to the end (ng · h / ml) Single dose 200 mg (group A) 74 6 1646 12.5 mg per hour over 15 h (group B) 32 sixteen 1227

Table 1-2. The average total data on a visual analogue scale for various side effects averaged for all 15 subjects in each group (see text for an explanation of the average total score)

Average overall grade Side action wie Group A (loading dose) Group B (16 fractional doses) Group B (placebo) Abdominal pain 2.7 0.1 1.7 Nausea 17.5 2.6 1,2 Urgent bowel movement 3,1 0.5 0.6 Burping 4.0 0.3 0.3 Abdominal cramps 3,1 0.1 0.9 Diarrhea 3.9 0.2 0.2 Dizziness 13.8 0.5 6.8 Tremor 7.9 1.7 0.5

Example 1 also demonstrates that (1) side effects can be reduced by controlling the rate at which sertraline is released in the gastrointestinal tract, (2) the release at a rate of 200 mg / 15 h = 13.3 mg / h results in a decrease gastrointestinal and systemic side effects compared with taking a loading dose with the severity of the side effect of a fractional dose at or close to placebo levels (Table 1-2), and (3) sustained release dosage forms that contain less than 200 mg sertraline also possess bla favorable indicators of side effects. During the first half of the study, a fractional dose of 200 mg / 15 h according to this example, eight doses of 12.5 mg were released within 7 hours with a reduced observed intensity of side effects (total dose 100 mg). In the same way, during the first quarter of the study, a fractional dose of 200 mg / 1 5 hours in this example, four doses of 12.5 mg were released within 3 hours at a reduced observed intensity of side effects (total dose 50 mg).

As another perspective, it is possible to reduce the intensity of side effects (especially tremors and dizziness, which are systemically mediated and not mediated by direct contact of sertraline with the gastrointestinal tract) by controlling the maximum concentration of sertraline in the pulmonary circulation after oral administration. In this example, 16 fractional doses of 12.5 mg each gave C _max 32 ng / ml with very low side effects. On the other hand, a loading dose of 200 mg gave C _max 74 ng / ml and showed significant side effects.

Example 2. This example demonstrates that taking sertraline in the form of a sustained release dosage form (200 mg dose in eight doses of 25 mg given at time zero and every hour for 7 hours) results in a reduction in the severity of side effects compared with a single loading dose of 200 mg.

In a double-blind, randomized trial with a parallel placebo control group, healthy men were divided into three groups. Group A (n = 14) received a single dose of 200 mg of sertraline in the form of two tablets of sertraline with immediate release of 100 mg (ΖΟΕΟΡΤ®) (group taking a loading dose). The tablets were washed down with 50 ml of water. Group A also received 50 ml of a placebo solution every hour for 7 hours. The placebo solution contained lactose and menthol. Group B (n = 16) received the same total dose, administered as a solution of 25 mg of sertraline (in 50 ml of water) with a frequency of one dose of 12.5 mg every hour for 7 hours (group taking a fractional dose). Group B also received two placebo tablets at the first dose. Group B (n equals 15) received placebo tablets and placebo solutions at appropriate appropriate time points. All subjects took tablets after night fasting.

Blood samples were taken before taking the medicine and at times 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 13, 15, 17, 24, 48, 72, 96, 120, and 144 hours after taking the medicine. Plasma sertraline concentrations, C _max , T _max, and PPC were also determined in the same manner. The pharmacokinetic data for this example are presented in table. 2-1.

Before taking the medicine and at every moment of taking a blood sample, each subject filled out a questionnaire, which consisted of a series of visual analogue scales with divisions, as described in example 1. A total of 45 subjects completed this study. For three side effects, evaluated at 30 points in time, a total of 4,500 ratings were obtained on individual visual analogue scales with divisions.

Tab. 2-1 demonstrates that the total systemic effect of sertraline for the two drug groups, as reflected in the AUC, was similar. For the fractional dose group, Smax was lower and Tmax was longer than expected, since the drug was taken within 7 hours rather than a single loading dose. Four subjects in the 200 mg single dose vomited at time points

2.6, 2.8, 2.8 and 3.8 hours. Pharmacokinetic data for these four subjects are not included in the average values presented in the table. 2-1. One subject with a fractional dose regimen for 7 hours vomited at 12.6 hours. Since vomiting occurred 3.5 hours later than T _max for this individual, the data for him were included in the averaging analysis for the fractional dose group. The observation of 4 and 1 cases of vomiting, respectively, for groups taking a loading dose and a fractional dose, indicates that taking a fractional dose for 7 hours causes a lower frequency of vomiting, while at the same time providing a therapeutic dose of sertraline, as evidenced by the pharmacokinetic AUC.

Data analysis for side effects on a visual analogue scale was performed as described in example 1. Tab. 2-2 demonstrates that the overall severity of side effects induced by sertraline was lower for exposures to 8 divided doses.

Thus, the intensity of side effects can be reduced by controlling the rate at which sertraline is released into the gastrointestinal tract. Example 2 thus demonstrates that release at a rate of 200 mg / 7 h = 28.6 mg / h (or slower) results in a decrease in the severity of the side effect (Table 2-2).

Example 2 also demonstrates that sustained release dosage forms that contain less than 200 mg of sertraline also have favorable side effects. During the first half of the example, four 25 mg doses were released over 3 hours with a reduced observed intensity of side effects (total dose 100 mg).

As for example 1, this example also demonstrates that it is possible to reduce the intensity of side effects, especially tremors and dizziness, by controlling the maximum concentration of sertraline in the pulmonary circulation after oral administration. In this example, a dosage regimen of 8 divided doses of 25 mg gave C _max 46 ng / ml, while a loading dose of 200 mg gave C _max 75 ng / ml. The dosage regimen in the form of 8 fractional doses of 25 mg showed a lower incidence of side effects than the loading dose regimen.

Table 2-1. Sertraline pharmacokinetics for a dose of 200 mg taken as a single dose or as eight doses of 25 mg every hour for 7 hours (average values)

Impact Max (ng / ml) Tmax (h) ^PPK 0 ^- to the end (ng · h / ml) Single dose 200 mg (group A) 75 5,4 1744 25 mg per hour over 7 h (group B) 46 10,4 1439

averaged for all 15 subjects in each group (see text for an explanation of the average total score) Average total score

Side effect Group A (loading dose) Group B (8 fractional doses) Group B (placebo) Burping 3.9 0.1 0.1 Dizziness 10,4 4.8 2.1 Tremor 8.9 2.7 0.3

Example 3. This example demonstrates that the absorption of sertraline is different when sertraline enters directly into various sections of the gastrointestinal tract. Dosage forms that release most of the sertraline loaded into them before the transverse or descending colon is reached will provide a higher systemic effect of sertraline than dosage forms that release a significant portion of the sertraline loaded into them into the transverse or descending colon.

In two groups of 6 volunteers (groups A and B), each was given 200 mg of sertraline or placebo by four different cross-drug regimens. Acceptance through (1) tablets for oral administration, or (2) infusion of the solution through the nasoenteric tube into the stomach, duodenum or ileocecal region of the small intestine, or (3) infusion into the transverse colon through anal intubation.

In four different circumstances, group A received (1) oral tablets with immediate release of sertraline along with a placebo solution infused into the stomach, or (2) placebo tablets for oral administration with a placebo solution infused into the stomach, or (3) tablets placebo for oral administration with sertraline infused into the small intestine at the level of the ileocecal compound, or (4) placebo tablets for oral administration together with a placebo solution infused into the small intestine on level of ileocecal connection. In four different circumstances, group B received (1) oral tablets with immediate release of sertraline along with a placebo solution infused into the duodenum, or (2) placebo tablets for oral administration along with a placebo solution infused into the duodenum, or ( 3) placebo tablets for oral administration along with sertraline infused into the transverse colon, or (4) placebo tablets for oral administration along with a placebo solution infused across th colon.

A dose of sertraline for oral administration was administered as two 100 mg tablets.

Table 2-2. Average total visual analogue scale for various side effects, us93

Infusions were administered as a solution of 2 mg / ml at a rate of 20 ml / min for 5 minutes.

Blood samples were taken before taking the medicine and at times 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, 144, 192 and 240 hours after taking the medicine. Plasma sertraline concentrations were determined as in example 1. The pharmacokinetic data for this example are presented in table. 3-1.

Tab. 3-1 presents the observed mean C _max , T _max and AUC for various drug regimens. Infusion in the stomach and duodenal region gave PIC values (total systemic exposure), which were 79 and 110% of the AUC observed after taking tablets for oral administration, close to the values observed after oral administration of tablets (group A). Thus, absorption from these areas of the gastrointestinal tract (in addition to the more distal areas after the ingested substance moves distally over time) was close to absorption from the tablets for oral administration. Infusion into the ileocecal region yielded PPC values, which accounted for 62% of the PPC observed after taking tablets for oral administration. Thus, the ileocecal region (in addition to the more distal regions) has a limited ability to absorb sertraline. Infusion into the transverse colon resulted in PPC, which amounted to 16% of the PPC observed after taking tablets for oral administration. Thus, the transverse (and more distal descending) intestine had a more limited ability to absorb sertraline.

Table 3-1. Pharmacokinetics of 200 mg of sertraline delivered to various sections of the gastrointestinal tract

Group A Route of administration ^C max (ng / ml) Tmax (h) ^PPK 0 ^- to the end (ng · h / ml) Oral tablet 39.9 7.0 1174.5 Stomach infusion 35.6 7.0 923.1 Ileocecal infusion 27.3 5,0 727.1

Group B Route of administration Max (ng / ml) Tmax (h) ^PPK 0 ^- to the end (ng'h / ml) Oral tablet 44.7 6.7 1153.4 Duodenal Infusion 48.8 3,7 1270.3 Colon infusion 10.9 4.4 179.4

Example 4. This example illustrates the preparation of tablets with a hydrophilic matrix with a long release of sertraline, which release sertraline at different speeds depending on their composition, size and shape. This method includes (1) mixing all the components, as indicated in the table. 4-1, 4-2 and 4-3, with the exception of magnesium stearate; (2) selection and re-mixing of the same components; (3) adding and mixing magnesium stearate; and (4) compressing the final mixture into tablets.

In batches of 200-350 g in size, sertraline hydrochloride was mixed in a suitable vessel with all other components, with the exception of magnesium stearate, for 15 minutes using a TiBi1a mixer system (Vake1, Switzerland). Then, the mixture was passed through a 20 mesh sieve and mixed again for 15 minutes. Then, magnesium stearate was added and the mixture was stirred for 2 minutes. Using a conventional tablet press (MaieChu R-Rgekk, Mag1ek1u Masitek, ΕίνΌΓροοΙ, Εη ^ ηά), the resulting mixture was pressed into tablets using either capsule mechanical punches measuring% inch (0.635 cm) by 3/4 inch (1.905 cm) for examples 4A -4H, standard round concave (SLE) punches of 13/32 inch (1,032 cm) size for examples 4Ο and 4P, capsule mechanical punches of 1/4 inch (0.635 cm) 1/2 inch (1,270 cm) size for examples 4P- 4SC, or 1/4-inch (0.635 cm) per 9/16 inch (1.429 cm) mechanical punches or mechanical punches for examples 4E-4AB. A summary of the compositions made by direct compression of the drug mixture at 200 mg of sertraline per tablet is shown in table. 4-1 for examples 4A to 4P, at 100 mg of sertraline per tablet is shown in table. 4-2 for examples 4P to 4P, and at 50 mg of sertraline per tablet is shown in table. 4-3 for examples 4E through 4AB, respectively.

Table 4-1. Sustained release hydrophilic matrix tablet formulations made by direct compression on P-Rhecc at a dose activity of 200 mgA / tablet

Example % Sertraline Compound % GPMC K100EU ¹ % GPMC K4M ² % Lactose % HFC % MDSt Tablet weight (mg) 4A 29.8 24.9 5,0 - 39.3 1,0 750 4B 29.8 34.9 5,0 - 29.3 1,0 750 4B 29.8 41.6 8.2 - 19,4 1,0 750 4G 39.8 24.9 5,0 - 29.3 1,0 562 4D 29.8 24.9 5,0 39.3 - 1,0 750

4E 29.8 34.9 5,0 29.3 1,0 750 4G 29.8 41.6 8.2 19,4 1,0 750 4Z 39.8 24.9 5,0 29.3 1,0 562 4I 30,0 20,0 10.0 38,0 2.0 750 4K 30,0 15.0 15.0 38,0 2.0 750 4L 30,0 50,0 10.0 8.0 2.0 750 4M 30,0 33.3 16.7 18.0 2.0 750 4H 30,0 25.0 25.0 18.0 2.0 750 4O 39.8 24.9 5,0 - 29.3 1,0 562 4P 39.8 24.9 5,0 29.3 - 1,0 562

¹ HPMC represents hydroxypropylmethylcellulose, Me11yuse1 K100U (Όο \ ν Sesh1sa1, M1y1apb, ΜΙ) ² HPMC represents hydroxypropylmethylcellulose, Me11yuse1 K4M (Όον Sesh1sa1, M1y1apb, ΜΙ) ³ GFK denotes dihydrate calcium hydrogen phosphate, Ειικ: οιηρΐΌ88 (Efuagb Mepbe11 Cb, 8iggeu,. IR) ⁴ MDSt stands for magnesium stearate; the sertraline compound% reflects the amount of sertraline salt required to reach 200 mgA.

Table 4-2. Sustained release hydrophilic matrix tablet compositions prepared by direct compression on E-Prge88 at a dose activity of 100 mgA / tablet

Example % Sertraline Compound % GPMC K100GU ¹ % GPMC K4M ² % Lactose % MDSt Tablet weight (mg) 4P 30,0 20,0 10.0 38,0 2.0 375 4C 15.0 24.4 12,2 46,4 2.0 750 4T 30,0 15.0 15.0 38,0 2.0 375 4U 15.0 18.3 18.3 46,4 2.0 750 4F 30,0 33.3 16.7 18.0 2.0 375 4X 15.0 40.6 20,4 22.0 2.0 750 4C 30,0 26.6 13,4 28.0 2.0 375 4h 15.0 32,5 16.3 34.2 2.0 750 4 Щ 15.0 30.5 6.1 46,4 2.0 750

¹ HPMC represents hydroxypropylmethylcellulose, Μeίοse1 K100U (Όον Sesh1sa1, M1y1apb M1) ² HPMC represents hydroxypropylmethylcellulose K4M Μeίοse1 (Όον Sesh1sa1, M1y1apb, M1) ³ MdSt denotes magnesium stearate% sertraline compound reflects quantity of sertraline salt needed to achieve 200 mgA.

Table 4-3. Sustained release hydrophilic matrix tablet compositions prepared by direct compression on E-Prge88 at a dose activity of 100 mgA / tablet

Example % Sertraline Compound % GPMC K100GU ¹ % GPMC K4M ² % Lactose % MDSt Tablet weight (mg) 4E 30,0 20,0 10.0 38,0 2.0 187.5 4th 15.0 24.4 12,2 46,4 2.0 375 4th 15.0 18.3 18.3 46,4 2.0 375 4AA 15.0 40.6 20,4 22.0 2.0 375 4AB 15.0 32,5 16.3 34.2 2.0 375 4AB 15.0 30.5 6.1 46,4 2.0 375

¹ HPMC represents hydroxypropylmethylcellulose, Μeίοse1 K100U (Όο \ ν Sesh1sa1, M1y1apb M1) ² HPMC represents hydroxypropylmethylcellulose, Μeίοse1 K4M (Όο \ ν Sesh1sa1, M1y1apb, M1) ³ MdSt denotes Magnesium Stearate% of the compound sertraline reflects the amount of salt of sertraline required to achieve 200 mgA.

Example 5. Selected tablets with a matrix with a sustained release according to example 4, as shown in the table. 5-1 were tested using a sustained-release dissolution test procedure w along with quantitative determination of sertraline by reverse phase HPLC to determine the released sertraline, expressed as a percentage of the total dose, as described below.

Dosage forms with prolonged release of sertraline were tested in a standard I8P apparatus with rotating blades, as described in Ipieb 8ίaίe8 Pba ^ tacore ^ a XXIII (I8P) Πί88ο1Ηΐίοπ Te81 CHarlég 711, Arraga1i8 2. The rotation of the blades was established at a speed of 50 rpm in 900 ml of acetate buffer (0.13 M acetic acid) with 0.075 M sodium chloride, using potassium hydroxide in order to bring the pH to 4.0 at 37 ° C. Dissolution vessels were closed to prevent evaporation. At indicated times after the start of the test (i.e. immersion of the dosage form in the apparatus vessel), filtered aliquots of the test medium (typically 2 or 10 ml) were selected and analyzed for sertraline using reverse phase HPLC as described below.

Sertraline was quantified by reverse phase high performance liquid chromatography as follows. A fixed volume of 20 μl was injected into the analytical column (150 mm x 3.9 mm long in diameter of the Νονα-Ras C-18 column).

The isocratic mobile phase consisted of an aqueous acetate buffer, methanol and acetonitrile in a volume percentage of 40/15/45. An aqueous acetate buffer was prepared in accordance with the following: (1) 2.86 ml of glacial acetic acid was added to a 1000 ml Erlenmeyer flask with a magnetic stirrer in an ice bath; (2) 3.48 ml of triethylamine was added to the flask with stirring; and (3) the flask was filled to volume and mixed well. Methanol of purity suitable for HPLC (15 vol.%) And acetonitrile of purity suitable for HPLC (45 vol.%) Were added to aqueous acetate buffer (40%). After thorough mixing, the mobile phase was filtered under vacuum and degassed using a 0.45 μm PTFE (polytetrafluoroethylene) filter (L1b-X 305 suitable liquid and solid separators). The flow rate of the mobile phase was 1.8 ml / min with UV detection of sertraline at 254 nm.

The dissolution results, presented in the form of the dependence of the percentage of dissolved sertraline on time, are presented in table. 53 (n is 3 tablets). Examples 4P, 4C, 4C, 4CH, 4YU, 4AA, 4AB both satisfy the dissolution criteria and are sustained release embodiments of this invention. Other drugs from the table. 4-1. 4-2 and 4-3 have not been tested, but they are also sustained release embodiments of this invention.

Table 5-1. Sustained release of sertraline ίη νίΐΐΌ from the compositions of tablets with a hydrophilic matrix indicated in the table. 4-1. 4-2 and 4-3

Example Ω1 (%) Od (%) Ωε (%) Ω12 (%) Ω1β (%) 024 (%) 4P 13.2 26.6 41.4 56.1 70.0 89.7 4C 9.6 20.4 32.4 47.8 60.2 75.2 4C 6.3 20.9 40.2 54.0 65.1 82.1 4h 8.9 24.8 44.1 61.3 73.7 92.2 4 Щ 11.3 25.8 43.0 59.0 73.3 88.4 4AA 5.0 16.4 28.7 40.4 51.9 70.7 4AB 5.7 19.6 37.3 54.9 70.4 92.2 4AB 9.6 28.5 52.0 72.4 86.2 96.8

O is the presented values.% Of drug released represents the average of 3 tablets.

Example 6. This example demonstrates that some side effects of sertraline (for example, nausea, belching and diarrhea) are partially or mainly mediated by direct contact of sertraline when taken orally with the upper gastrointestinal tract, rather than mediated by the presence of sertraline in the pulmonary circulation after absorption. Bypassing the stomach by oral administration of sertraline in the form of a dosage form that exhibits a sustained release before a sustained release of sertraline (i.e., a sustained release dosage form followed by a sustained release), it is thus possible to reduce the intensity of the locally mediated side effects of sertraline.

In a subgroup of a larger, double-blind, randomized trial with a parallel placebo control group, healthy men were divided into two groups (Study 1). Group A received a single dose of 200 mg of sertraline in the form of two 100 mg tablets of sertraline (second commercial tablets of 100 mg) (group taking a loading dose). The tablets were poured with 50 ml of water. Group B received two placebo tablets. All subjects took tablets after night fasting.

Blood samples were taken before taking the medicine and at times 0.5. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 18. 18. 20. 22. 24.

36. 48. 72. 96. 120. 144. 168. 192 and 240 hours after taking the medicine. Plasma sertraline concentrations were determined using capillary gas chromatography. The total systemic effect of sertraline was determined by measuring the area under the curve of plasma sertraline concentration versus time (PPC) for each subject in this group and then calculating the average PIC for this group. C _max represents the maximum observed plasma sertraline concentration achieved in a subject. T _max is the time at which C _{max is} reached. After

100 doses of sertraline 200 mg, the average C _max was 74 ng / ml, the average T _max was 6 hours, and the average PIC was 1646 ng · h / ml (averaged over 15 subjects).

A similar second study was conducted (study 2). After taking a dose of sertraline in 200 mg, the average Cmax was 75 ng / ml, the average Tmax was 5.4 hours, and the average AUC was 1744 ng · h / ml (averaged over 11 subjects). Four subjects in the 200 mg dose group vomited at 2.6, 2.8, 2.8, and 3.8 hours. Data for these four subjects were not included in the pharmacokinetic averages.

Before taking the medicine and at every moment of taking a blood sample, each subject filled out a questionnaire, which consisted of a series of visual analogue scales with divisions, in which the subject had to rate on a scale of 010 the severity of some possible side effects. Subjects were instructed that 0 indicates no action and 10 indicates the strongest possible action. Subjects were instructed to interpolate moderate side effects between 0 and 10.

A total of 30 subjects completed study I: 15 in groups A and B. For each side effect, side effects were evaluated at 30 time points; in total, 900 ratings were obtained on individual visual analogue divisions. In total complexity, 29 subjects completed the Study 2: 14 in group A and 15 in group B. For each side effect, side effects were evaluated at 30 points in time, a total of 870 ratings were obtained on individual visual analogue divisions.

FIG. Figure 6 shows the dependence of sertraline concentration in plasma on the average score of the results of individual assessments on visual analog scales with divisions for nausea in Study I. This graph, known as the pharmacokinetics-pharmacodynamics plot (PK / PD plot), was obtained as follows. For 15 subjects in group A, plasma sertraline concentrations were averaged for each time point in blood sampling to obtain the average sertraline concentration for group A at each time point. Similarly, for 15 subjects in group A, a score on the visual analogue scale with divisions for nausea was averaged for each point in time. Average estimates for nausea at each point in time (y axis) were plotted against plasma sertraline levels at the corresponding time point (x axis). The arrow on the graph shows the development of the FC / PD dependence as time increases. The FC / PD plot in FIG. 6 shows a clockwise moving hysteresis for a 200 mg loading dose. Thus, as time increased, the nausea score and plasma sertraline concentration both increased before the nausea score reached its maximum at a plasma sertraline concentration that was lower than the max plasma sertraline concentration. As Cmax grew (to approximately 70 mg / ml), the score for nausea decreased to a lower value. When subsequent plasma sertraline concentrations decreased, the score for nausea took values that were lower than the estimates observed for the same sertraline concentrations at earlier time points. This clockwise hysteresis (or proteresis) is consistent with the explanation that sertraline-induced nausea is largely mediated by direct contact of sertraline with the gastrointestinal tract, and is not completely mediated by the presence of sertraline in the systemic blood, as the average score for nausea is not unambiguous associated with plasma sertraline concentration. At earlier times after taking the medication (0-3 hours), sertraline taken orally primarily comes into contact with the stomach and can suppress its excretion into the duodenum (described in Example 1). Since nausea is not directly related to plasma sertraline concentration and is apparently primarily mediated locally through contact with the gastrointestinal tract, lower release of sertraline in the gastrointestinal tract, such as the duodenum or jejunum, will result faster absorption and reduced contact with the upper parts of the gastrointestinal tract, and thus, reduction of nausea.

In study I, it was also shown that diarrhea exhibits a clockwise hysteresis in the curve of the dependence of the score for this side effect, depending on the plasma sertraline concentration. The maximum score for diarrhea increased by the third hour after taking the medicine, long before the observed average Tmax of plasma, which is 6 hours in these subjects. Thus, slowing down the release of sertraline taken orally before the stomach is passed can result in a decrease in diarrhea .

As described above, burping was detected in four subjects in Study 2. Individual FC / PD charts for these subjects, for the side effect of burping, showed clockwise hysteresis. Thus, slowing down the release of sertraline taken orally before the stomach is passed can result in a reduction in burping.

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Example 7. This example illustrates a method for preparing a plurality of particles with sustained release of sertraline according to the invention. This method of preparing multiple particles with a prolonged release of sertraline consists of preparing the cores of multiple particles without a shell by rotational granulation of microcrystalline cellulose as a spheronizing agent and water as a granulating agent before an average granule size of more than 1 mm is reached.

Many sertraline particles were prepared using a fluidized bed device equipped with a rotor (C1ay SRCC-1 from C1ay L1g Tesitdiez, Katzeu, N1). 300 g of sertraline drug and 300 g of microcrystalline cellulose as a spheronizing agent were loaded into the rotor bowl. Then, water is sprayed tangentially into the rotating layer of the drug and microcrystalline cellulose before the final agglomeration point (determined by the average granule size) is reached. After the granulation is completed, the plurality of particles are dried in a rotating fluidized bed until the water content in them is less than 2% (as measured by the loss in mass upon drying or PPV). The composition and key process parameters for these sets of particles are listed in table. 7-1.

Table 7-1. The composition of many particles with a prolonged release of sertraline and key manufacturing parameters used during the rotational granulation method

Example No. Sertraline * (g) Lu1se1 (g) Water (g) Rotation speed (r / min) Spray rate (g / min) The endpoint of the PPV (% N ₂ O) The average size of the granules (μm) 7A 300 300 1100 640 15-20 49 1200

* the amount of sertraline in terms of the form of the hydrochloride salt

Example 8. This example illustrates a method for preparing a plurality of particles with sustained release of sertraline according to this invention, which are released at different rates depending on the thickness of the shell with a sustained release. The method includes (1) preparing cores of a plurality of sertraline particles without a shell by rotational granulation; (2) applying a speed-limiting shell to the cores. This example also evaluates the sustained release of multiple particles.

Many sertraline particles are prepared using a fluidized bed device equipped with a rotor (Model SRCC-1 from S1ai L1g Tesitdiez, Katzeu, N1). 300-500 g of sertraline drug and 0500 g of microcrystalline cellulose as a spheronizing agent are loaded into the rotor bowl. Water, plasticized hydroxypropyl cellulose (Oraigu ™) or a binding solution of polyvinylpyrrolidone (Roscove C 15) (10% solids concentration) of the drug and microcrystalline cellulose are sprayed tangentially into the rotating layer before reaching the final agglomeration point (determined by the average granule size) . The intended average granule size in the manufacture of these preparations varies from 100 to 1400 microns. After granulation is completed, the resulting plurality of particles are dried in a rotating fluidized bed before the moisture content is less than 2% (estimated by loss on drying, PPV). A summary of the compositions of the sets of particles made using water as a granulating agent as detailed in table. 8-1 for examples 8A through 8E. A summary of the composition of the nuclei of the many particles, the manufacturing parameters and the final average granule size prepared in the manufacture of the preparations, using a binding solution consisting of either Oraigu water or Rowone solution as a granulating agent, are shown in Table. 8-2 for examples 8ZH-8U.

Table 8-1. Sertraline core particle compositions and manufacturing parameters used in a rotational granulation method using water as a granulating agent

Example No. Sertraline (g) Lu1se1 (g) Water (g) Rotation speed (r / min) Spray rate (g / min) The endpoint of the PPV ^(b) (% N ₂ O) The average size of the granules (μm) 8A 300 300 1340 640 thirteen 39 320 8B 300 300 1340 640 12 41 470 8B 500 500 2950 640-585 13-15 42 465 8G 335 165 630 630 14 36 510 8D 300 ^(a) 300 700 630 thirteen 37 370 8E 300 300 1060 630 12 45 600

^{(a) the} stream of ground sertraline hydrochloride is less than 10 microns ^(b) And! 1B - loss on drying

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104

Table 8-2. Sertraline core particle compositions and manufacturing parameters used in a rotational granulation method using a binding solution as a granulating agent

Example No. Sertraline (g) Auyue1 (g) Binder (10%) Rotation speed (r / min) Spray rate (g / min) Outlet temperature (° С) Air pressure (Pa) The average size of the granules (μm) 8G 500 0 OS 640 5-15 33 10-14 530 8Z 500 0 OS 640 5 34 10 130 8I 500 0 OS 640 5 32 10 205 8K 500 0 OS 640 10 27 12 270 8L 400 one hundred OS 640 fifteen thirty thirteen 320 8M 375 125 OS 800 26 31 twenty 680 8H 375 125 OS 810 21 37 10 340 8O 375 125 RUR 800 25 33 8 n.d. 8P 375 125 OS 855 24 36 8 1400 8P 375 125 OS 855 25 37 8 390 8C 375 125 OS 855 24 36 10 510 8T 375 125 OS 855 24 37 12 360 8U 375 125 OS 855 24 36 eleven 430

OS stands for Orabgu ™ C1eag, plasticized hydroxypropyl methylcellulose

RUR means Row1bope C15, plasticized polyvinylpyrrolidone

Then, the granules of the nuclei of a plurality of sertraline particles (Example 8G) are coated with a velocity-limiting coating by spraying in a rotating fluidized bed (C1a11 6RS6-1, 61An Tes11gys | wk, Watkeu, N1) until the desired end point is reached (shell mass%). In this example, the rate limiting coating consists of a suspension of plasticized ethyl cellulose (8he1eake ™) diluted to 25% solids and hydroxypropyl methylcellulose (Orabgu ™, Co1ogsop, 1ps.) In weight ratios of 85% 8he1eake ™ to 15% Orabgu ™. This shell is applied to the granules of the nuclei of many particles made in accordance with this Example, before the shell will be from 5 to 25 wt.%.

Example 9. This example illustrates a method of preparing tablets with a non-destructive matrix with a sustained release of sertraline. This method includes (1) mixing all components except magnesium stearate; (2) selection and re-mixing of the same components; (3) adding and mixing magnesium stearate; and (4) compressing the resulting mixture into tablets. This example also evaluates the release rates of sertraline ίη ν Igo from matrix tablets using the ίη Y1yo test described in detail.

In a batch of 100 g, sertraline was mixed in a suitable vessel with all other components except magnesium stearate for 10 minutes using a TiBi1a mixer system (Vake1, Switzerland). The mixture was then passed through a 40 mesh sieve and mixed again for 5 minutes.

Then magnesium stearate was added and the mixture was stirred for 5 minutes. Using

Mapek1u P-Rgekk (Mapek1u MasYpek, L1egroo1,

Епд1апб) the resulting mixture was pressed into tablets using conical mechanical punches with a ratio of the diameter of the top to base of 1: 3 and a ratio of height to base of 2: 5. A summary of the compositions made by direct compression of the mixture at 127 mg of sertraline per tablet is shown in table. 9-1.

Table 9-1. Sustained Release Non-Destructive Matrix Tablet Composition Made by Directly Pressing on E-Rhecc at a Dose Activity of 127 mgA / Tablet

% Sertraline Compounds * % ELOSE1 ¹ % Lactose free % MDSt Tablet weight (mg) 33.7 40,0 24.3 2.0 420

¹ EIose1 ™, E11u1se11i1oke ΝΓ 81apbagb Rgetst, viscosity 10, I E <> \ ν C11et1ca1 * amount of sertraline compound in terms of hydrochloride salt

The resulting sustained-release non-destructive matrix tablets were tested using the sustained-release drug release testing method described in Example 5. The results are presented in table. 9-2 (n is 1 tablet). This non-destructible matrix tablet satisfies the dissolution criteria and is a sustained release embodiment of the present invention.

Table 9-2. Sustained release of sertraline t νίΐΐΌ from the composition of the tablet with a non-destructive matrix indicated in the table 9-1 in 900 ml of 0.13M acetate buffer with

0.075 sodium chloride, pH 4.0 at 37 ° C in an i8P # 2 apparatus with a set blade rotation speed of 50 rpm

Ω1 (%) Ω4 (%) 08 (%) Ω12 (%) Ω16 (%) Ω24 (%) The release rate of ^1, (mgA / h) 6.2 13.9 23.1 28.5 33.8 41.2 2.2

(,) are the reported values of% drug released, presented for one tablet ^t means that the rate of release of sertraline was calculated on the basis of 24 hours at a time, since 80% of the release did not occur within 24 hours of the test period.

105

106

Example 10

This example illustrates that organic acids have the ability to increase the solubility of sertraline hydrochloride salt. Acids were selected by dissolving the putative acid in water and then stirring an excess of sertraline hydrochloride in an acidic solution for at least 8 hours. The concentration of sertraline in the supernatant was then determined by HPLC analysis. The results of this test are presented in table. 101 below. Most of the acids listed in the table successfully increased the solubility of sertraline hydrochloride (normal solubility is 2.5 mg / ml).

Table 10-1

Excipient The approximate concentration of the excipient (mg / ml) Solubility of sertraline (mg / ml) P.1 - malic acid 900 21 Lemon acid 600 twenty Erythorbic acid 400 nineteen Adipic acid 14 12 Maleic acid 700 6.4 B-aspartic acid 10 5.5 Wine acid 1400 5.5 B-glutamic acid 12 5,4 Fumaric acid eleven 3,1 Tannic acid 2000 2,8 0,1-tyrosine 600 2.2

Preferred acids based on this screening test are malic, citric, erythorbic and adipic acids. Maleic, b-aspartic, tartaric and b-glutamic acids also significantly improved the solubility of sertraline hydrochloride. Some controlled release dosage forms with such acids in the core will perform better than dosage forms without such acids. This is especially true for osmotic pressure-based drugs that release a drug solution.

Example 11. This example illustrates that organic acids have the ability to increase the solubility of the salt of sertraline acetate in a manner similar to that used for the hydrochloride salt described in example 10. The excipient, excipient concentration and solubility of sertraline are listed in table. 11-1 below. Based on these results, preferred acids for inclusion in a dosage form in which it is desirable to increase the solubility of sertraline acetate are ascorbic, erythorbic, citric, lactic, aspartic, glutamic and aconitic acids.

Table 11-1

Excipient Excipient Concentration (mg / ml) Solubility of sertraline (mg / ml) Vitamin C 400 more than 425 Erythorbic acid 400 more than 330 Lemon acid 600 146 Lactic acid 213 more than 294 Aspartic acid 7 110 Glutamic acid 12 108 Aconite Acid 500 more than 92 Taconic acid 150 72 succinic acid 77 28 Missing - 64

Example 12. This example illustrates that organic acids and three calcium salts have the ability to increase the solubility of sertraline lactate salt in water using a method similar to that used for the hydrochloride salt described in example 10. Excipient, excipient concentration in the aqueous test solution and the solubility of sertraline lactate in the test solution are listed in table. 12-1 below. The solubility of sertraline lactate in water is approximately 125 mg / ml. The data below show that eight solutions of organic acids provide sertraline lactate solubilities of approximately 125 mg / ml or higher; adiline, erythorbic, itaconic, citric, aspartic, glutamine, histidine and ascorbic. Also, a solution of a mixture of two of these acids also has high solubility: ascorbic and aspartic acids. The solubility of sertraline lactate was also high in calcium salt solutions, either by itself (calcium citrate), or in a mixture with ascorbic acid.

Table 12-1

Excipient Excipient Concentration (mg / ml) Solubility of sertraline lactate (mg / ml) Adipic acid 14 360 Erythorbic acid 400 more than 217 Taconic acid 150 more than 202 Lemon acid 600 162 Aspartic acid 7 more than 155 Glutamic acid 12 more than 125 Histidine 42 more than 116 Ascorbic Acid / Aspartic Acid 400/7 116 Vitamin C 400 102 Glycine 250 66 Aconite Acid 200 less than 59 Wine acid 1400 12 Fumaric acid eleven less than 9 Sorbic acid 3 less than 9 Calcium Lactate / Ascorbic Acid 50/400 160 Calcium citrate 10 165 Calcium Carbonate / Ascorbic Acid 50/400 176 Missing - 125

107

108

Example 13. The lower solubility of the salt of sertraline chloride and all salts of sertraline lactate and sertraline acetate in the presence of high chloride concentrations indicates that core compositions are preferred in which sertraline remains in solution, that is, it does not precipitate or forms a gel-like substance when chloride is present in the medium in which it is used. It has been found that some organic acids and salts inhibit the precipitation or gelation of sertraline when chloride ion is present in the next screening test. Sertraline lactate was dissolved in water, either by itself (as a control), or together with the intended excipient. Then sodium chloride was added (as a concentrated solution) and the result was observed. An excipient was considered suitable if the solution remained clear and liquid. The more chloride that can be added to the excipient solution so that the solution remains clear, the more suitable the excipient.

Tab. 13-1, presented below, demonstrates the results of this screening test, indicating that all excipients tested increased the concentration of sertraline in chloride solutions.

Table 13-1

Excipient Excipient Concentration (mg / ml) End \ aC1 (mm) The final concentration of sertraline (mg / ml) Observation after adding \ aC1 Missing - 38 22 Gel / precipitate Ascorbic / Aspartic Acid 400/7 152 162 Solution Aspartic 7 114 162 Solution acid 7 152 one hundred Gel Vitamin C 400 one hundred 102 Sediment Ascorbic Acid / Calcium Lactate 400/50 150 165 Solution Ascorbic Acid / Calcium Carbonate 400/50 150 170 Slightly muddy Citric Acid / Calcium Lactate 600/50 150 162 Solution Histidine 42 150 110 Slight sediment

Example 14. Organic compounds (solubilizers) were selected for their ability to increase the solubility of sertraline salts in aqueous solutions in the presence or absence of chloride. An excess of sertraline lactate was added to the aqueous solution of the intended solubilizer and, in most cases, an organic acid. Organic acids in these solutions were also saturated and additional solubilizing agents were presented at the concentrations shown in the table. 14-1. The equilibrium solubility of sertraline was measured. Then, sodium chloride was added to the saturated solution, and the final concentration of sertraline was measured. The results of these screening tests are summarized in table. 14-1.

Example 15. This example illustrates that the solubilizers for sertraline can also increase the rate of dissolution of sertraline. The effect of the putative excipient on the dissolution rate of sertraline was determined by adding a solid drug, a putative solubilizing excipient and, in some cases, other excipients, such as an organic acid and an osmotic agent (such as sugar), into a 1.8 ml centrifuge tube. Sample tubes were centrifuged at 14K C in a microcentrifuge for 5 min to compact the powder. 150 μl of gastric buffer was added to the compacted powder and the samples were gently shaken, then centrifuged at 14 ° C in a microcentrifuge for 2 minutes. Samples were then removed from the microcentrifuge and left alone before the solution was taken. The solution was taken from the samples 10 min after the stomach buffer was added to the powder mass and HPLC was analyzed to determine the concentration of sertraline.

The dissolution rate (mg sertraline / mlmin) was calculated based on a certain concentration of dissolved sertraline in the supernatant as a function of time over the first 10 minutes of dissolution. These dissolution rates and excipient mixtures, for which they were determined, are summarized in table. 15-1 below. As shown, some excipient mixtures containing solubilizers significantly (approximately 3 times or more) increased the rate of dissolution of sertraline compared to sertraline per se and compared to sertraline and ascorbic acid.

Example 16. This example illustrates a method for preparing osmotic tablets comprising a tablet core containing sertraline surrounded by a semipermeable asymmetric membrane membrane. Sertraline hydrochloride is ground into powder by hand for 10 min with citric acid and microcrystalline cellulose (Ανίοοί PH 102, EMC) using a mortar with a diameter of 6 1/2 inches (16.51 cm) and a pestle. Magnesium stearate as a lubricant is then mixed with a spatula powder for 60 s. The mass ratio of sertraline hydrochloride to citric acid to microcrystalline cellulose to magnesium stearate was 8.5: 63.8: 23.7: 4; with a total weight of 10 g. The mixed mixture is then pressed into 470 mg tablets in a modified hydraulic jack (manufactured in EauUp). equipped with a manometer and

109

110 concave punch 3/8 inch (0.9525 cm) at a pressure of 2500 lbs / ⁱⁿ² (17237500Pa) for 2 seconds. The sizes of the obtained tablets are 3/8 inch (0.9525 cm) in diameter and 1/4 inch (0.635 cm) in thickness. A semi-permeable membrane membrane (as described in US Patent Application No. 397974 dated 10/6/96, entitled THe Ike OT L5utte1g1c Methgapek ίη ОеНуегу Оеуееесе5) is applied to these tablets using an LES8-20 pellet coating pan (Ueser grit grinder). per minute, inlet temperature 40 ° C and air flow 40 ft ³ / min (0,01887789 m ³ / s). The shell solution contains, by weight, 10% cellulose acetate (ITAP CHepisac CA398-10), 2.5% polyethylene glycol (BA8E, PEC 3350), 15% water and 72.5% acetone. The coated tablets are dried for 1 hour at 50 ° C. before testing. After drying, the weight of the applied coating substance is 15.4% of the total mass. These tablets contain a dose of sertraline 50 mg / tablet.

Example 17. Osmotic delivery tablets are prepared using essentially the same methods for preparing tablet cores and applying an asymmetric membrane coating to the cores described in Example 16. The composition of the cores and the coating solution are different from those used in Example 16, as shown in Table. 17-1. Example 16 is presented in table. 17-1 for comparison. Presented significant changes in the composition of the core include the form of the salt of sertraline, the type and amount of solubilizer, and the type and amount of the osmotic agent. The amount of binder (Auyue1), a lubricant (magnesium stearate) and a solubilizer were changed in accordance with what is necessary to obtain good tabletting and moisturizing properties. These tablets contain a dose of sertraline 50 mgA / tablet.

Example 18. The release rates of sertraline from the selected preparations described in examples 16 and 17 are determined in accordance with the methods described in example 5 except that 750 ml of the solution in the apparatus for determining dissolution is used and the stirring speed is 100 rpm. Sertraline release analysis is determined by reverse phase high performance liquid chromatography (HPLC).

The results of the reverse phase tests conducted using these methods are listed in Table. 18-1. The first two of the listed preparations 18a and 18b (preparations 16 and 17a) exhibit lower release rates than those claimed in this invention and are included as comparison examples. Both of these preparations contain a salt of sertraline (hydrochloride or lactate) and only lactose as an osmotic agent and do not contain solubilizing excipients. All preparations 18v, 18g and 18z listed in the table. 18-1, contain the solubilizing excipient of this invention. Formulations 18g, 18e and 18g are sustained-release embodiments followed by sustained release according to the invention. In the same way, the remaining preparations in Example 17 (17 b-h) are also sertraline preparations, which are embodiments of this invention.

Table 18-1

Sertraline Release Test No. Tablets according to example No. The fraction of the drug released (%) by the specified time 0 h 1 hour 2 h 4 h 8 h 12 h 20 h 18a sixteen 0 0 0 0 0 0 0 18b 17a 0 0 one 2 - 10 (17h) 12 18c 17d 0 6 fifteen 35 62 76 78 18g 17k 0 0 0 4 nineteen 28 44 18d 17n 0 8 nineteen 37 60 73 83 18th 17o 0 0.7 6 17 37 54 78 18zh 17p 0 0.4 4 thirteen 31 41 53 18h 17h 0 8 eighteen 38 56 64 66

Example 19. This example illustrates osmotic pressure-based sertraline tablets, which consist of an inner core containing an osmotic agent and a solubilizing excipient, surrounded by sertraline and an excipient layer, and then surrounded by a semipermeable shell. The tablets of this example differ from other examples in that the inner core, binder, and solubilizer are prepared, tabletted, and placed inside a larger drug containing the tablet. Citric acid and microcrystalline cellulose (Au1ce1, PH 102, EMC) are ground into powder for 5 minutes using a mortar with a diameter of 4 1/2 inches (11.43 cm) and a pestle. Polyoxyethylene monostearate 40 (Moog) 52, BA8E) is then added and triturated for 1 minute. The mass ratio of citric acid to microcrystalline cellulose to Moog) was 86.1: 9.8: 4.1, with a total weight of 4 g. The mixed mixture was pressed into tablets of 232 mg as in Example 16 for Example 111

112 with the exception that the punch for tabletting is 1/4 inch (0.635 cm). The core of the resulting tablet is 1/4 inch (0.635 cm) in diameter and 1/4 inch (0.635 cm) thick. A mixture for the outer tablet is prepared as in example 17. It contains sertraline lactate, citric acid, lactose, A \ tce1 and polyoxyethylene sorbitan (Tueep 80, 1C1) in a mass ratio of 14: 50: 20: 15: 1. The resulting tablet is prepared by placing 200 mg of the drug containing the mixture on the bottom of a 3/8 inch (0.9525 cm) standard plate, then a 232 mg tablet of citric acid is changed to its top and an additional 270 mg of the mixture containing the drug is poured onto the top. The tablet is then compressed using the same conditions as in Example 16. The resulting tablet was 3/8 inch (0.9525 cm) in diameter 1/2 inch (1.27 cm) in thickness. A semi-permeable membrane membrane was applied to the tablets using the same method as in Example 16. The release rate test results close to the results described in Example 5 indicate that this osmotic preparation of sertraline is an embodiment of this invention.

Example 20. This example illustrates a method for preparing an osmotic tablet consisting of a core of a bilayer tablet surrounded by a semipermeable coating. The following substances are mixed with the form of a drug containing granulate and wet granulated in a mixer: from 50 to 200 g of sertraline and its pharmaceutically acceptable salts; from 250 to 325 g of polyethylene oxide having a molecular weight of approximately 100,000; and from 0 to 275 g of polyethylene oxide having a molecular weight of approximately 200,000; 10 to 30 g of hydroxypropyl methylcellulose having an average molecular weight of approximately 11300; and from 0 to 10 mg of magnesium stearate. A second granulate for preparing a second layer in the core of a tablet comprises from about 110 to 140 g of polyethylene oxides having an average molecular weight in the range of from about 5,000,000 to 7,500,000; from 5 to 25 g of hydroxypropyl methylcellulose having an average molecular weight of approximately 11300; from 40 to 70 g of sucrose; and from 0 to 10 g of magnesium stearate. These granules are used to prepare the core of a bilayer tablet with a first layer containing sertraline and a second layer, which are mainly swelling hydrophilic substances. These bilayer tablets are then coated with a semipermeable coating comprising 70 to 98% cellulose acetate having an acetyl content of 32 to 39.8% and 2 to 30% polyethylene glycol having an average molecular weight of approximately 3350. In the coating on the side of the tablet, containing sertraline, create at least one channel.

Example 21. Osmotic release tablets were prepared with a water-permeable outer shell through which release channels were drilled to pass sertraline dissolved in the aqueous solution contained in the tablet core. Tablet cores consisting of 14.0 wt.% Sertraline lactate, 11.0 wt.% Aspartic acid, 47.4 wt.% Sucrose, 25.0 wt.% A \ tce1 PH 101 and 2.6 wt.% Stearate magnesium (the total mass of the core is 470 mg) is prepared essentially by the same method given in example 17. These tablet cores are then coated with a solution consisting of 6% ethyl cellulose (ELOSE 8-100, Ωο \ ν Siesche1ca1), 4% polyethylene glycol (PEC 3350, BA8E) and 8 wt.% Water in acetone using the method described in example 17, so that the weight of the shell is 70.4 mg per tablet (total weight of the tablet with the shell is 540.4 mg). In some tablets, 3 holes are drilled on each side of the tablet, each in a diameter of 340 μm (a total of 6 holes per tablet). For a second set of tablets, 18 holes were drilled on each side of the tablet, each in a diameter of 340 μm (36 holes in total per tablet).

Each type of tablet is tested for sertraline release using 0.75 L acetate / saline buffer as described in Example 5. The percentage of sertraline released into the surrounding solution as a function of time for each type of tablet is shown in Table 1. 21-1 below. Both types of tablets represent similar release rates, suggesting that drug release is predominantly osmotic (if the release is predominantly diffusion, 36-hole tablets should release the drug about 6 times faster than 6-hole tablets).

Table 21-1

Time (h) Released Sertraline (%) 6-hole tablet 36-hole tablet 0 0 0 one 3 7 2 12 17 4 26 32 8 44 44 12 47 46

Example 22. This example describes tablets with a swelling hydrogel with controlled release of sertraline. The hydrochloride, or acetate, or lactate, or sertraline aspartate (50 mgA sertraline) is mixed with polyethylene oxide with a molecular weight of 20 K (REO-20K) (350 mg) with other solubilizers and excipients, and the mixture is tabletted on a Mapekh1 Ture-E3-rgehh press. Tablets coated113

114 are sprayed with a solution of cellulose acetate in a mixture of acetone / ethanol to a final dry weight of the shell of 14% of the total weight of the tablet with the shell. Drill a hole with a diameter of 2 mm (mechanically, by laser or other methods) through a shell on one surface of a portion of the tablets. A hole with a diameter of 2 mm is drilled through the entire central part of the other part of the tablets.

Example 23. This example describes tablets with a swelling hydrogel with controlled release of sertraline. The hydrochloride, or acetate, or lactate, or sertraline aspartate (50 mgA sertraline) is mixed with polyethylene oxide with a molecular weight of 20 K (PEO-20K) (350 mg) with other solubilizers and excipients, and the mixture is tabletted on a Mape & Toure-E3-rge§ press 8. The tablets are coated with a spray of a solution of a cellulose acetate / hydroxypropyl cellulose mixture (1: 1) in a solution of acetone / methanol 9: 1 to a mass of the resulting shell of 15% of the total weight of the tablet with the shell.

Example 24. This example describes tablets with a swelling hydrogel with controlled release of sertraline. The hydrochloride, or acetate, or lactate, or sertraline aspartate (50 mgA of sertraline) is mixed with polyethylene oxide with a molecular weight of 20 K. (REO-20K) (350 mg) with other solubilizers and excipients, and the mixture is tabletted on a Mape & Ture-E3-rge press §8. The tablets are coated by spraying a solution of cellulose acetate in an acetone / ethanol mixture to a final dry shell weight of 14% of the total tablet shell. Drill a hole with a diameter of 2 mm (mechanically, by laser or other methods) through a shell on one surface of a portion of the tablets. A hole with a diameter of 2 mm is drilled through the entire central part of the other part of the tablets.

Example 25. This example describes tablets with swelling hydrogel controlled release of sertraline. The hydrochloride, or acetate, or lactate, or sertraline aspartate (50 mgA of sertraline) is mixed with 100 K molecular weight polyethylene oxide (PEO-20K) (350 mg) with other solubilizers and excipients, and the mixture is tabletted on a Mape & Toure-E3-rge§ press 8. The tablets are spray-coated with a suspension of sucrose (50/60 mesh) in a solution of cellulose acetate in acetone (2.5%) and PEC-600 (2.5%). The mass ratio of cellulose acetate to RES-600 to sucrose in the shell is 1: 1: 2. The resulting shell is 15% by weight of the entire tablet with the shell.

Example 26. This example describes tablets with a swelling hydrogel with controlled release of sertraline. The hydrochloride, or acetate, or lactate, or sertraline aspartate (50 mgA of sertraline) is mixed with polyethylene oxide with a molecular weight of 20 K (PEO-20K) (350 mg) with other solubilizers and excipients, and the mixture is tabletted on a Mapeyu Toure-E3-rge§ press 8. The tablets are spray-coated with a solution of cellulose acetate (2.2%) and hydroxypropyl cellulose (HPC) (2.2%) in an acetone / methanol 9/1 solution. The mass ratio of cellulose acetate to HPC in the shell is 1: 1, and the resulting shell is 15% of the total weight of the tablet with the shell.

Example 27. This example describes the preparation of tablets with openings with a long release of sertraline, which releases sertraline through a central hole. The hydrochloride, or acetate, or lactate, or sertraline aspartate (50 mgA of sertraline) is mixed with lactose, magnesium stearate and possibly ethyl cellulose and other excipients, and the mixture is tabletted on a Mapeiu Toure-E3ge55 press. The tablets are coated with a solution of ethylene vinyl acetate in methanol. After drying, the weight of the shell is 15% of the total weight of tablets without a shell. Drill a hole with a diameter of 2 mm (mechanically, by laser or other methods) through a shell on one surface of a portion of the tablets. Drill a hole with a diameter of 2 mm through the entire central part of the other part of the tablets.

Example 28. This example describes the preparation of a sustained release tablet followed by a sustained release of pH initiated sertraline (enteric coated). Tablets with a sustained release of sertraline with a matrix or osmotic, or with a hydrogel with a shell are prepared as in examples 4, 9, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26 and 27.

The coating composition is prepared in accordance with the composition presented in table. 28-1.

Table 28 -1. Coating composition

Component Function 6 wt.% Eiigacy 1301) -55 Enteric polymer 16,0 Triethyl citrate Plasticizer 1,6 Talc Anti-stick agent 4.0 Water Solvent 78,4

The coating solution is sprayed onto tablets with a sustained release of sertraline using Epiphyte HCT-30 H1-Coa! E. The shells [polymer Eiigadi + triethyl citrate + talc] are applied in such a quantity that they make up from 5 to 25 wt.% Tablets without a shell. These coated tablets release little or no sertraline at pH of the stomach, and release sertraline by a sustained release method (1 mgA / h to 40 mgA / h) after they pass into the duodenum.

Example 29. This example illustrates a method for preparing a plurality of particles with

116 a strange slowing down of the release followed by a prolonged release of sertraline, initiated by pH.

Many sustained-release particles of sertraline are prepared as described in Examples 7 and 8. A bottom spray fluidized bed apparatus (Claa and SRCC-1) is used for delayed-release coating. Typically, sustained release shell levels are from about 5% to about 50%. The sustained release shell is a suspension containing 12.3% methacrylic acid copolymers (Eibgyad® L 30 Ό-55). 6.2% talc, 1.5% triethyl citrate and 80% water.

Since the sustained release shell is soluble in a medium in which the pH is greater than 5.5. the plurality of particles prepared in this way prevent the release of sertraline from the core of the coated particles in the stomach, in which the pH is low, and enable the release of sertraline from the core of the coated particles in the small intestine and colon, in which the pH is greater than 5.5.

Example 30. This example illustrates a method for preparing a plurality of particles with a spatial delayed release followed by a sustained release of pH initiated sertraline, with a protective layer between the core of the plurality of sustained release particles and a pH initiated sustained release membrane. This dosage form design attenuates any physical or chemical incompatibilities between the sustained release core and the sustained release membrane. This method includes (1) preparing nuclei of multiple particles with a sustained release of sertraline; (2) applying a protective coating to the particles of the nuclei; and (3) applying a second, pH-sensitive, sustained release coating to the first coating.

Nuclei of multiple particles with a prolonged release of sertraline are prepared as described in Examples 7 and 8. Using a fluidized bed apparatus, a solution containing a 5% solution of plasticized hydroxypropyl methylcellulose (Orabgu®) is sprayed onto the nuclei of a particle with a prolonged release before a 10% coating is applied.

A sustained release shell (typically 5 to 50% of the final mass of the plurality of shell particles) is applied using the same fluidized bed apparatus as above. The sustained release shell is a suspension containing 12.3% methacrylic acid copolymers (Eibgadb® L 30 Ό-55). 6.2% talc, 1.5% triethyl citrate and 80% water.

Example 31. This example illustrates a method of preparing a tablet with a spatial, followed by a sustained release of pH initiated sertraline with a shell in a cellulose acetate phthalate coating.

Sertraline sustained release tablets are prepared as in Examples 4. 9. 16. 17. 19. 20. 21. 22. 23. 24. 25. 26 and 27. Sertraline sustained release tablets are then coated by spraying a solution of acetate phthalate in acetone (AFC) in the apparatus for applying a coating by spraying in NST-60 N1CoAlEg® (Rgeipb 1pb. Cons .. Tokuo). AFC plasticize with 25% (by weight) of diethyl phthalate (DEF). A sufficient amount of AFC is sprayed onto tablets to obtain a polymer of the final shell with a mass of, after drying, from 5 to 50 wt.% Relative to the weight of the layer of tablets without a shell.

Example 32. This example illustrates the preparation of a tablet with a spatial retardation with a prolonged release of sertraline, pH-initiated, with a shell of AFC with a barrier membrane.

Tablets with a prolonged release of sertraline are prepared as in examples 4. 9. 16. 17. 19. 20. 21. 22. 23. 24. 25. 26 and 27. The tablets are coated with a spray of a solution of hydroxypropyl methylcellulose (HPMC; Clogsop. 1 ps.) In water using HCT-60 H | -Coa1eg. In this method, the tablets are coated with a HPMC barrier coating of 5% by weight relative to the weight of the initial sustained release tablet. The tablets are then also coated with a spray of cellulose acetate phthalate (AFC) and a plasticizer DEP (as described in Example 31. in HCT-60 H | -Coa1eg). A sufficient amount of AFC is sprayed onto tablets to obtain a polymer of the final shell with a mass of, after drying, from 5 to 50 wt.% Relative to the weight of the layer of tablets without a shell. The HPMC shell serves as a barrier between the sustained release tablet of sertrapine and the pH sensitive membrane of the AFC. This barrier membrane prevents premature dissolution (or weakening) of the AFC membrane, for example in a stomach environment with a low pH, possibly caused by a locally high pH in the internal contents of the tablet due to the presence of sertraline.

Example 33. This example illustrates the preparation of a tablet with spatial retardation (with an acrylic resin coating) followed by a sustained release of pH initiated sertraline with an AFC barrier coating.

Tablets with a prolonged release of sertraline are prepared as in examples 4. 9. 16. 17.

19. 20. 21. 21. 22. 23. 24. 25. 26 and 27. The tablets are spray-coated with a solution of hydroxypropyl methylcellulose (HPMC) (Ciogsop.

117

118

1ps.) In water using HCT-60 H1-Coa1eg. In this method, the tablets are coated with a HPMC barrier coating of 5% by weight relative to the weight of the initial sustained release tablet.

The composition of the shell is prepared in accordance with the composition in table. 28-1.

The coating solution is sprayed onto tablets with a sustained release of sertraline with a coating of HPMC using Przepyb HCT-30 H1-Coal.

The total weight of the applied polymer of acrylic resin is from 5 to 50% by weight of the tablet layer with a long release of sertraline. The inner shell of their HPMC serves as a barrier between sertraline and a pH sensitive acrylic shell. This barrier coating prevents premature dissolution (or weakening) of the acrylic resin coating, for example in a stomach environment with a low pH, possibly caused by a locally high pH in the internal contents of the tablet due to the presence of sertraline.

Example 34. This example illustrates the preparation of dosage forms in the form of tablets with a delayed release in time (activated by water) followed by a sustained release of sertraline.

Sertraline sustained release tablets are prepared as in Examples 4, 9, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26 and 27. These tablets are then coated with a water-soluble and / or water-disintegrating retardant in an apparatus for applying shells, such as NST-30, NST-60 or NST-130 Coa1eg (Rgeipb 1ps). The tablets are coated with an aqueous HPMC solution to a final shell weight of 5 to 50% of the final shell tablet weight. Large masses of membranes give longer slowdowns before initiating the release of sertraline into the environment in which it is used (lumen of the gastrointestinal tract). The slowdown time can also be increased, including low-water soluble polymers (including but not limited to ethyl cellulose (EC), cellulose acetate (AC), cellulose acetate butyrate) in an amount of from small to moderate. For example, a coating composition may consist of 95: 5 GPMC / EC to 50:50 GPMC / EC or 95: 5 GPMC / AC to 50:50 GPMC / AC. In the case of such coating systems consisting of mixed polymers, it may be necessary to adjust the solvent composition to dissolve the mixture of water-soluble and poorly water-soluble polymers. For example, mixtures of acetone and water or ethanol and water can be used as necessary.

In the environment in which the use is made, the dosage forms of this example exhibit a slower release of sertraline, during which the coating polymer dissolves from the surface of the sustained release tablet followed by a sustained release of sertraline. After deceleration, the sustained-release tablet of sertraline releases the sertraline enclosed in it at a rate of 1 to 40 mg / h.

Example 35. This example illustrates a method for preparing osmotic tablets comprising a tablet core containing sertraline lactate surrounded by a semipermeable asymmetric membrane membrane. Tablet cores are prepared using equipment standard in the pharmaceutical industry. The components of the tablet core, including 13.8 wt.% Sertraline lactate, 11 wt.% L-aspartic acid, 5 wt.% Calcium acetate, 29.5 wt.% Microcrystalline cellulose and 38.2 wt.% Fructose, are mixed then pass through the roller compactor and grind. These milled materials are then mixed with 2.5% by weight of magnesium stearate to form the final mixed substance, which is used to prepare tablets having a total weight of 470 mg in a conventional tablet press (KShap T-100). Semi-permeable asymmetric membrane membranes (as described in US Pat. No. 5,621,059) are applied to the tablets using a coating pan with a lateral outlet (L8C8-20. Ueslog Comp.). The coating solution, including 10 wt.% Cellulose acetate 398-10, 2.5 wt.% Polyethylene glycol 3350, 15 wt.% Water and 72.5 wt.% Acetone, is sprayed onto tablets at a rate of 20 g / min before the level of the coating on the tablets will be 10 wt.%.

Example 36. This example illustrates a method for preparing osmotic tablets comprising a tablet core containing sertraline lactate surrounded by a semipermeable asymmetric membrane membrane. Tablet cores are prepared using equipment standard in the pharmaceutical industry. The components of the tablet core, including 13.8 wt.% Sertraline lactate, 5 wt.% Glyceryl monolaurate, 11 wt.% L-aspartic acid, 5 wt.% Calcium acetate, 27 wt.% Microcrystalline cellulose and 35.7 wt. % fructose is used to make tablet cores. First, glycerol monolaurate is wet granulated with 14 wt.% Microcrystalline cellulose using ethanol (95%) as a solvent for wet granulation. After drying and grinding, the wet granulate is mixed with the components listed above (including balancing microcrystalline cellulose), then passed through a roller compactor and ground. These

119

120 milled substances are then mixed with 2.5 wt.% Magnesium stearate to form the final mixed substance, which is used to prepare tablets having a total weight of 470 mg in a conventional tablet press (Κί1ί; · ιη T-100). Semi-permeable asymmetric membrane membranes (as described in US Pat. No. 5,621,059) are applied to tablets using a coating pan with a lateral outlet (LOC8-20, Ves! Comp.). A coating solution, including 10 wt.% Cellulose acetate 398-10, 2.5 wt.% Polyethylene glycol 3350, 15 wt.% Water and 72.5 wt.% Acetone, is sprayed onto tablets at a rate of 20 g / min. One batch of tablets is prepared with a 10 wt.% Coating and the second batch of tablets is prepared with a 20 wt.% Coating.

Example 37. Sertraline acetate. Sertraline base (Compound AA), 200.2 mg) was dissolved in ethyl acetate (200 μl) in a 5 ml reaction tube. Glacial acetic acid (41.2 μl) was added to the sertraline base solution with constant stirring. An additional 500 μl of ethyl acetate was added to facilitate mixing. The reaction mixture was allowed to granulate at room temperature for five hours. The crystals are filtered, washed with 10 ml of ethyl acetate and then dried in a vacuum oven at 40 ° C for 20 hours. The determined yield is 16%. so pl. 126 ° C.

Example 38. Sertraline acetate. Sertraline base (Compound AA), 200.2 mg) was dissolved in hexane (1.5 ml) in a 10 ml reaction tube. The solution is heated to 40 ° C. Glacial acetic acid (41.2 μl) is added to the sertraline base solution. The reaction mixture was allowed to cool to room temperature and then granulated for one hour. The crystals are filtered and dried in a vacuum oven at 40 ° C for 72 hours. The determined yield is 90%. so pl. 126 ° C.

Example 39. Sertraline acetate. Sertraline hydrochloride (125 g) is suspended in a mixture of water (1 L) and hexane (2.5 L). NaOH (25% aqueous, 35 ml) was added. Sertraline base is distributed in the hexane phase. The hexane layer is separated. The aqueous layer was extracted a second time with hexane (500 ml). Layers of hexane are combined. A solution of the base in hexane is heated to 50 ° C. Glacial acetic acid (23 ml) is added to the sertraline base solution. The reaction mixture was stirred at 50 ° C for 30 minutes. The reaction mixture was allowed to cool to room temperature and stirred at room temperature overnight. The crystals are filtered and washed five times with a total of 250 ml of hexane. The crystals are dried at 40 ° C in a vacuum oven for 48 hours. The yield is 89%. so pl. 126 ° C.

Example 40. X-ray structural analysis of a single crystal. A typical crystal was studied and a data set at 1A (maximum κίη θ / λ is 0.5) was collected on a diffractometer 8 | 53719-1173. The atomic scattering factors were taken from I! Па па па!! Па 1 1 1 1 Ь Д ог ог Х-га у г ук ук ук ук! Од од од гар гар. 1n! Erpa11opi1 TaLeek Dog X-gau Sguk! A11odgaru, vol. 1U, pp. 55, 99, 149. In addition: Kupos and Rhekk, 1974. All crystallographic calculations were facilitated using the 8HEXT system. 6.M. 811е1bpsk 8NEHTT igeg Mapia1, No.co1e! 1pc1gitep1 Cons., 5225 Uegopa KB, Mabyop, VI 53711, 1981. All diffractometric data were collected at room temperature. A suitable crystal, data collection and refined parameters are summarized in table. 40-1 below.

The experimental structure was established by direct methods. This experimental structure was refined in accordance with how it should be. The map of differences revealed a small amount of water localized on two-dimensional axes. The refinement indicates that the degree of filling of this water is 0.25. Wherever possible, the positions of hydrogen were calculated. The localization of methyl hydrogen and hydrogen in nitrogen was determined by Fourier difference methods (Roscheg). Hydrogen locations in water were not localized. Hydrogen parameters were added to the calculations of the structural factor, but were not specified. All shifts calculated in the final least-squares refinement cycle were less than 0.1 of their respective standard deviations. The final Kindex was 8.97%. The final Fourier difference did not reveal any loss or electron density not in its place.

The refined structure shown in FIG. 1, plotted using the 8HEXT draw package described in the indicated 8HEXT and igeg Mapia1. Absolute configurations were not installed.

Table 40-1

Parameters of Sertraline Acetate Crystal Formula (, ·· ΙΙ · .ν (.Ί _; (. · _; Ι6 (Т * 0.25Н2О (371.3) Crystallization medium Water Crystal size (mm) 0.10x0.16x0.22 Cell sizes a = 15,629 (8) A B = 8.695 (3) A s = 15.048 (3) A α = 90.0 ° β = 110.45 (3) ° γ = 90.0 ° Y = 1916 (1) A Space group C2 Molecule / Single Cell 4 The calculated density, g / cm ³ 1,287 Linear absorption factor, mm ' ¹ 3,144

121

122

Table 40-2. Atomic coordinates (x 10 ⁴ ) and coefficients of equivalent isotropic substitution (E ² x 10 ³ )

x at Ζ and (equiv.) * C (1) 8321 (14) 10711 (22) -3626 (12) 79 (2) C (2) 7559 (13) 10583 (20) -3227 (12) 66 (2) C (3) 7581 (14) 8997 -2770 (12) 83 (2) C (4) 8453 (11) 8847 (21) -1902 (11) 67 (2) C (5) 9260 (11) 9344 (22) -2182 (12) 66 (2) C (6) 9268 (14) 10390 (22) -2917 (12) 87 (2) C (7) 10033 (16) 10928 (24) -3028 (14) 103 (2) C (8) 10898 (14) 10516 (24) -2347 (14) 91 (2) C (9) 10883 (16) 9557 (24) -1637 (14) 97 (2) C (10) 10115 (12) 9074 (21) -1513 (12) 67 (2) C (11) 8555 (14) 7256 (22) -1473 (14) 79 (2) C (12) 8418 (12) 6975 (22) -625 (12) 66 (2) C (13) 8514 (14) 5542 (25) -215 (12) 89 (2) C (14) 8760 (12) 4314 (21) -708 (18) 90 (2) C (15) 8861 (18) 4526 (27) -1587 (15) 132 (2) C (16) 8763 (14) 6002 (22) -1905 (13) 88 (2) N (17) 8112 (9) 9728 (19) -4522 (12) 65 (2) C (18) 8616 (14) 10130 (25) -5161 (13) 98 (2) C1 (19) 8377 (5) 5313 (12) 862 (4) 127 (2) C1 (20) 8816 (6) 2473 (13) -178 (6) 144 (2) C (1A) 9993 (16) 5929 (28) -3685 (16) 157 (2) C (2A) 9026 (12) 5594 (27) -4,223 (12) 83 (2) O (3A) 8771 (11) 4331 (19) -4476 (12) 119 (2) O (4A) 8464 (12) 6651 (19) -4306 (11) 116 (2) About (1GS) 10000 (37) 2700 (33) -5000 (37) 132 (4)

• Equivalent isotropic and defined as one third of the trace of the orthogonal tensor ϋί]

Example 41. Osmotic tablets of sertraline acetate. This example illustrates a method for preparing osmotic tablets comprising a tablet core containing sertraline acetate surrounded by a semipermeable asymmetric membrane membrane. Tablet cores are prepared using equipment standard in the pharmaceutical industry. The components of the tablet core, including sertraline acetate (14 wt.%), Ascorbic acid (50 wt.%), Lactose (20 wt.%), Microcrystalline cellulose (15 wt.%) And polyethylene glycol stearyl ether (1 wt.%, Mug) 52, 8 | dta Chétua1, 81. Boc8, MO) are mixed manually using a mortar and pestle. Mixed substances are used for the preparation of tablets having a total mass of 470 mg in a single-stage tablet press (Prge55). Semi-permeable asymmetric membrane shells (as described in US Pat. No. 5,621,059, which is incorporated herein by reference) are coated onto tablets using a pelletizing boiler with side outlet (LOC8-20, Ueslog Comp., 67544 ¹¹ '81., Mapop, 1A 52392 ) The coating solution, including ethyl cellulose 8-100 (6 wt.%), Polyethylene glycol 3350 (4 wt.%), Water (10 wt.%) And acetone (80 wt.%), Is sprayed onto tablets at a rate of 20 g / min before the level of the coating on the tablets will be 10 wt.%.

Example 42. This example illustrates a method of preparing multiple particles for use in the preparation of sustained release dosage forms designed to release sertraline predominantly below the stomach. The method includes (1) preparing cores of a plurality of non-coated sertraline particles; (2) applying a protective coating to the particles of the nuclei; and (3) applying to the first shell a second shell, slowing down the release, sensitive to pH.

Nuclei of a plurality of particles containing the drug are prepared using a fluidized bed device equipped with a rotor (Model ORSO-1). A 400 gA sertraline drug (such as sertraline acetate, sertraline lactate or sertraline aspartate) and a binding solution containing 5% poly (ethyl acrylate, methyl acrylate) (EibgadI® ΝΒ-30-Ό), 5% plasticized hydroxypropyl methylcellulose (Orabgu®) are initially loaded into the rotor bowl , Clogsop, GSe4 Roth1, RA 19486) and 90% of water are sprayed into the rotating layer before the average granule core size of approximately 250 μm is reached.

A binder solution containing 5% hydroxypropyl methylcellulose solution (Orabgu®) is sprayed onto the coreless particles in the same fluidized bed equipped with a rotor before a 10% coating is applied. This intermediate shell enhances the adhesion of the final release retardant shell to the core particles.

A delayed release coating (typically 5 to 50% is required to satisfy the delayed release criterion) is applied using the same fluidized bed device as described above. The release retardant coating is a suspension containing 12.3% copolymers of methacrylic acid (Eijgad® L-30 55-55, Kobt OMVN, Epapel. Oegtapu; and 8. Oyuye: 8oteg§e1, N1), 6.2 % talc, 1.5% triethyl citrate and 80% water. The final product is a lot of particles with a slow release with particles having an average size of approximately 300 microns.

Example 43. Sertraline L-lactate.

Sertraline base (Compound AA), 200 mg) was dissolved in ethyl acetate (200 μl) in a 10 ml conical reaction tube. L-lactic acid (solid, 68.5) was separately dissolved in ethyl acetate (100 μl). A solution of L-lactic acid is added to the solution of sertraline base with constant stirring in a magnetic stirrer. A precipitate is observed for approximately 2 minutes after complete addition of the L-lactic acid solution to the sertraline base solution. The reaction mixture was allowed to granulate overnight (18 hours) at room temperature. The precipitate was filtered and the solid washed with 1 ml of ethyl acetate. The crystals are dried in a vacuum oven at 40 ° C in

123

124 for 20 hours. The dried solid is characterized and identified as sertraline Lactate salt. The determined yield is 72%. so pl. 153 ° C.

Example 44. Sertraline L-lactate.

Sertraline base (compound for preparing AA, 1 g) was dissolved in ethyl acetate (20 ml) in a 50 ml round bottom flask and the solution was heated to 40 ° C. L-lactic acid (342.5 mg) was separately dissolved in ethyl acetate (5 ml). The solution of L-lactic acid is added in small portions to the solution in a round-bottom flask, which is constantly stirred with a magnetic stirrer. The reaction mixture was stirred at 40 ° C. for 2 hours after complete addition of the L-lactic acid solution. The reaction mixture was allowed to cool to room temperature and the crystals were filtered. The crystals are washed with 5 ml of ethyl acetate and then dried in vacuo at 40 ° C. for 24 hours. The dried solid is characterized and identified as the sertraline L-lactate salt. The determined yield is 86%. so pl. 153 ° C.

Example 45. Sertraline L-lactate.

Sertraline base (10 g) was dissolved in isopropanol (150 ml) in a 500 ml round-bottom flask and the solution was heated to 40 ° C. Lactic acid (3.4 g) was separately dissolved in ethyl acetate (25 ml). The solution of L-lactic acid is added in small portions to the solution in a round-bottom flask, which is constantly stirred with a magnetic stirrer. The reaction mixture was stirred at 40 ° C. for 4 hours after complete addition of the lactic acid solution. The reaction mixture was allowed to cool to room temperature and the crystals were filtered. The crystals are washed with 50 ml of hexane and then dried in vacuo at 40 ° C for 48 hours. The dried solid is characterized and identified as sertraline L-lactate salt. The determined yield is 94%. so pl. 153 ° C.

Example 46. L-Sertraline L-Lactate.

Sertraline mandelate (750 g) is suspended in a mixture of water (3.9 L) and ethyl acetate (3.9 L). The suspension is cooled to 15 ° C. Add No. 1OH (25% aqueous, 250 ml) to give a solution with a pH of 9.6. The free base of sertraline is distributed in a layer of ethyl acetate, which is separated. The aqueous layer was extracted with additional 3.4 L of ethyl acetate. The combined ethyl acetate layers were washed with 3.9 L of water. An ethyl acetate layer containing sertraline free base was concentrated in vacuo and filtered to purify the solution. To this solution was added L-lactic acid (155 g). The reaction mixture was granulated for 20 hours at room temperature. The crystals are filtered, washed 4 times with ethyl acetate (400 ml each time). The crystals are dried overnight under vacuum at

40 ° C. The determined yield is 84%. so pl. 153 ° C.

Example 47. Sertraline L-lactate.

Sertraline hydrochloride (300 g) is suspended in a 3: 1 mixture of water (3 L) and ethyl acetate (1 L). The pH of the suspension is adjusted to a value of 8.0 by adding approximately 1 L of 1N. sodium hydroxide solution. Sertraline free base is distributed in the ethyl acetate phase. The two phases are allowed to separate completely due to the fact that the biphasic solution is allowed to remain without shaking overnight. The ethyl acetate layer was then separated and washed twice with 3 L of deionized water to remove chloride ions. The resulting ethyl acetate layer containing sertraline free base was concentrated to 300 ml under vacuum to remove the remaining water. An ethyl acetate solution containing a sertraline base is heated to 40 ° C. L-lactic acid is dissolved in ethyl acetate to form a 7.5 M solution. The lactic acid solution is added to the sertraline base solution in small portions with constant shaking. Mixtures give the opportunity to mix and granulate overnight (16-20 hours). The crystals are filtered and washed 4 times with an equivalent volume of ethyl acetate (200 ml each time). The crystals are dried overnight under vacuum at 40 ° C. The determined yield is 97%. so pl. 153 ° C.

Example 48. X-ray structural analysis of a single crystal. A typical crystal was studied and the data set at 1A (maximum δί η θ / λ is 0.5) was collected on an Eietesh Κ3ΚΑ / ν diffractometer. Atomic scattering factors were taken from IV, Kutyus Rgekk, Vtttjyat, 1974, p. 55, 99, and 149. All crystallographic calculations were facilitated using the 81 системыΛΊΈ system (see O.M. ^ and, VI 53711, 1981). All diffractometric data were collected at room temperature.

A suitable crystal, data collection and refined parameters are summarized in table. 48-1.

Table 48-1

Parameters of Sertraline I-Lactate Crystal Formula S17I1, Zh12S ₃ N5O ₃ (396.3) Crystallization medium ethyl acetate Crystal size (mm) 0.07x0.07x0.11 Cell sizes a = 8.660 (5) A B = 24.43 (1) A c = 9.382 (3) A α = 90.0 ° β = 91.94 (3) ° λ = 90.0 ° V = 1984 (2) A ³ Space group P21 Molecule / Single Cell 4 The calculated density, g / cm ³ 1,327 Linear absorption factor, mm ' ¹ 3,101

125

126

The experimental structure was established by direct methods. This experimental structure was refined in accordance with how it should be. The localization of methyl hydrogen and hydrogen in nitrogen was determined by Fourier difference methods (Ροιιιι®Γ). Hydrogen locations in water were not localized. Hydrogen parameters were added to the calculations of the structural factor, but were not specified. All shifts calculated in the final least-squares refinement cycle were less than 0.1 of their respective standard deviations. The final Kindex was 8.97%. The final Fourier difference did not reveal any loss or electron density not in its place.

The refined structure shown in FIG. 3, plotted using the 8 HEXT drawing package, the Absolute configuration is determined by the method of Ibers and Hamilton (1beg and Ηηιηίίΐοη) (Ηηιηίίΐοη, Ac 1a Cr ^ <k (, 1965, 18, 502-510 and 1begk et al., Ac1a Cga, 17, 781-782). The absolute X-ray structural configuration is in agreement with the configuration of L-lactate. The atomic coordinates are listed below in Tables 48-2.

Table 48-2. Atomic coordinates (x 10 ⁴ ) and coefficients of equivalent isotropic substitution (E ² x 10 ³ )

x at Ζ υ C (1) -4173 (13) 4373 (5) 7866 (10) 44 (2) N (1A) -4127 (10) 3773 (4) 7483 (9) 47 (2) C (1B) -5542 (14) 3455 (6) 7614 (12) 69 (2) C (2) -2556 (12) 4576 (6) 8220 (10) 54 (2) C (3) -1658 (12) 4605 (5) 6877 (11) 55 (2) C (4) -2328 (12) 5027 (5) 5834 (10) 44 (2) C (4A) -4064 (12) 4979 (5) 5658 (10) 45 (2) C (5) -4860 (13) 5273 (5) 4565 (11) 49 (2) C (6) -6411 (15) 5250 (6) 4430 (12) 68 (2) C (7) -7291 (13) 4981 (6) 5430 (13) 68 (2) C (8) -6563 (13) 4705 (5) 6491 (12) 56 (2) C (8A) -4955 (12) 4700 (5) 6662 (10) 39 (2) C (1 ') -1539 (12) 5015 (5) 4411 (10) 46 (2) C (2 ') -1022 (12) 5517 (5) 3816 (12) 52 (2) C (3 ') -308 (13) 5493 (5) 2508 (11) 52 (2) C1 (1) 243 (5) 6117 (2) 1757 (4) 91 (1) C (4 ') -9 (13) 5024 (6) 1820 (11) 54 (2) C1 (2) 972 (4) 4996 258 (3) 81 (1) C (5 ') -486 (14) 4545 (5) 2414 (11) 56 (2) C (6 ') -1219 (14) 4538 (5) 3694 (11) 52 (2) C (1X) 495 (13) 7219 (5) -5303 (11) 47 (2) N (1XA) 648 (11) 7826 (4) -4926 (9) 50 (2) C (1XB) -814 (13) 8109 (5) -4598 (12) 58 (2) C (2X) 2126 (14) 7016 (5) -5601 (12) 67 (2) C (3X) 3130 (13) 6938 (6) -4263 (11) 64 (2) C (4X) 2437 (13) 6525 (5) -3240 (10) 53 (2) C (4XA) 702 (12) 6586 (5) -3183 (11) 46 (2) C (5X) -45 (14) 6304 (5) -2112 (12) 55 (2) C (6X) -1610 (15) 6299 (5) -1995 (13) 65 (2) C (7X) -2501 (16) 6604 (6) -2945 (14) 80 (2) C (8X) -1807 (13) 6890 (5) -4024 (12) 56 (2) C (8XA) -206 (12) 6900 (5) -4117 (10) 39 (2) C (1X ') 3233 (13) 6545 (5) -1796 (10) 49 (2) C (2X ') 3944 (14) 6083 (5) -1250 (11) 58 (2) C (3X ') 4642 (13) 6084 (5) 101 (11) 52 (2) C1 (3) 5554 (5) 5501 (2) 743 (3) 85 (1) C (4X ') 4732 (14) 6569 (6) 875 (11) 62 (2) ^C1 (4) 5695 (4) 6600 (2) 2528 (3) ⁷⁸ ( ¹ )

C (5X ') 3978 (14) 7023 (5) 350 (11) 62 (2) C (6X ') 3293 (15) 7006 (5) -982 (11) 63 (2) C (1Υ) 1318 (16) 2575 (6) 9581 (14) 106 (2) C (2Υ) 540 (13) 3113 (5) 9839 (11) 57 (2) Ο (3Υ) 103 (10) 3150 (5) 11268 (8) 87 (2) C (4Υ) -786 (14) 3217 (5) 8778 (12) 49 (2) Ο (5Υ) -479 (11) 3255 (4) 7509 (8) 86 (2) Ο (6Υ) -2081 (10) 3239 (4) 9294 (8) 65 (2) C (1Ζ) 6352 (15) 8746 (8) -2633 (15) 110 (2) C (2Ζ) 4677 (13) 8843 (6) -2407 (12) 66 (2) Ο (3Ζ) 4349 (11) 8757 (5) -1000 (8) 101 (2) C (4Ζ) 3602 (14) 8483 (5) -3343 (11) 50 (2) Ο (5Ζ) 3800 (10) 8497 (4) -4676 (7) 66 (2) Ο (6Ζ) 2594 (10) 8209 (4) -2782 (7) 60 (2)

• Equivalent and isotropic, defined as one third of the trace of the orthogonal tensor υί]

Example 49. Osmotic tablets of sertraline Lactate. This example illustrates a method for preparing osmotic tablets comprising a tablet core containing sertraline L-lactate surrounded by a semipermeable asymmetric membrane membrane. Tablet cores are prepared using equipment standard in the pharmaceutical industry. The components of the tablet core, including sertraline L-lactate (13.8 wt.%), L-aspartic acid (11 wt.%), Calcium acetate (5 wt.%), Microcrystalline cellulose (29.5 wt.%) and fructose (38.2 wt.%) is mixed, then passed through a roller compactor and ground. These milled materials are then mixed with 2.5% by weight of magnesium stearate to form the final mixed substance, which is used to prepare tablets having a total weight of 470 mg in a conventional tablet press (Κίίίηη T-100). Semipermeable asymmetric membrane coatings (as described in U.S. Patent No. 5,612,059, which is incorporated herein by reference) is applied to the tablets using a coating pan side output (PS8-20, UesYug Pp ,, 675 44 '81 ,, ^s ^ Magyu 1A 52302). The coating solution, including 10 wt.% Cellulose acetate 398-10, 2.5 wt.% Polyethylene glycol 3350, 15 wt.% Water and 72.5 wt.% Acetone, is sprayed onto tablets at a rate of 20 g / min to of how the level of the coating applied to the tablets will be 10 wt.%.

Example 50. Osmotic tablets of sertraline Lactate. This example illustrates a method for preparing osmotic tablets comprising a tablet core containing sertraline L-lactate surrounded by a semipermeable asymmetric membrane membrane. Tablet cores are prepared using equipment standard in the pharmaceutical industry. The core tablets are prepared in accordance with the following.

Glycerol monolaurate (5 wt.%) Was wet granulated with microcrystalline cellulose (14 wt.%) Using methanol (95%) as a granulating solution127

128 creators. After drying and grinding, the wet granulate is mixed with sertraline L-lactate (13.8 wt.%), Aspartic acid L (11 wt.%), Calcium acetate (5 wt.%), Microcrystalline cellulose (additional 13 wt.%) and fructose (35.7 wt.%). After adding all the components, the granulate is passed through a roller compactor and milled. These milled materials are then mixed with magnesium stearate (2.5 wt.%) To form the final mixed substance, which is used to prepare tablets having a total weight of 470 mg in a conventional tablet press (KShap T-100, KShap & ^., 415 8a ^ dοη ^ ay Ipy 1, ^ gayat, RA 19044). Semi-permeable asymmetric membrane membranes (as described in US Pat. A coating solution, including 10 wt.% Cellulose acetate 398-10, 2.5 wt.% Polyethylene glycol 3350, 15 wt.% Water and 72.5 wt.% Acetone, is sprayed onto tablets at a rate of 20 g / min. One batch of tablets is prepared with a 10 wt.% Coating and the second batch of tablets is prepared with a 20 wt.% Coating.

Example 51. Dosage form of sertraline Lactate with an encapsulating solution. Sertraline L-lactate solutions are prepared in Sarti1 MSM ™ (mono- and diglycides of caprylic and capric acids, ABPes Сο ^ рο ^ аί ^ οη, ^ ШЬш, Οΐιίο 43219) at a concentration of 75 mgA / ml. The solutions are encapsulated in soft gelatin with a filling volume of 0.67 ml to give a single dose of 50 mgA.

Example 52. L-Aspartate of sertraline.

Sertraline base (AA production compound, 200.3 mg) was dissolved in ethyl acetate (800 μl, which was pre-saturated with water). L-aspartic acid (95.53 mg) is suspended in ethyl acetate (3 ml, which is pre-saturated with water). A suspension of aspartic acid is added to the sertraline free base solution. The reaction mixture was stirred for 24 hours. The solids were filtered, washed with ethyl acetate, saturated water, and then dried at 40 ° C. in a vacuum oven for 48 hours. The yield of sertraline L-aspartate was 96.4%, so pl. 247 ° C.

Getting AA.

Sertraline free base. Sertraline hydrochloride (2.5 g) is dissolved in water (one liter). The required amount of 1N is added to this solution. NaOH to a pH of 8.0. The resulting crystals are filtered and washed with deionized water (50 ml per gram of crystals). The crystals are dried at 40 ° C in a vacuum oven for 48 hours. The yield is 98%, so pl. 67 ° C.

Getting BB.

Sertraline free base. Sertraline hydrochloride (300 g) is suspended in a 3: 1 mixture of water (3 L) and ethyl acetate (1 L). The pH of the suspension is adjusted to 8.0 by the addition of approximately 1 L of 1N. sodium hydroxide solution, the free base of sertraline is distributed in the phase of ethyl acetate. The two phases are allowed to completely separate by allowing the two-phase solution to stand overnight without shaking. The ethyl acetate layer is then separated and washed twice with 3 L of deionized water to remove chloride ions. The resulting ethyl acetate layer containing sertraline base was concentrated to 300 ml in vacuo to remove residual water.

Table 14-1

Solubilizer Solubilizer end (mg / ml) Organic acid Solubility of sertraline (mg / ml) End-i \ aC1 (mm) End of sertraline (s \ aC1) one None (control) - Missing 125 150 5 2 Monocaprilin 10 Ascorbic 160 150 160 3 Triacetin one hundred Ascorbic 170 150 170 4 Monobutyrin fifty Missing 120 150 120 5 Diacetin fifty Ascorbic 120 150 120 6 ΙηινίΙοι® 312 10 Ascorbic 120 150 120 7 ΙηινίΙοι® 375 10 Ascorbic 120 150 120 8 ΙιιινίΙοι®. 742 fifty Missing 120 150 120 nine ΙιιινίΙοι®. 988 fifty Missing 140 one hundred 140 10 Triethyl citrate fifty Ascorbic 160 150 160 eleven P1igoshs® b31 fifty Missing 120 one hundred 120 12 Schet (> p11 (> ge E fifty Ascorbic 120 150 120 thirteen Sucrose Acetate Isobutyrate fifty Ascorbic 120 150 120 14 Capryllactate Sodium fifty Ascorbic 120 150 120 fifteen Sucrose monolaurate fifty Missing 150 150 150 sixteen Sodium laurillactate fifty Ascorbic 120 150 120 17 | 8rap® 80 fifty Ascorbic 120 150 120

129

130

Table 15-1

Prospective Excipient Organ. acid Concert organ. acid (wt.%) Osmotic agent End inspection agent (wt.%) Another excipient The concentration of another excipient (wt.%) Sertraline salt form (wt.%) Sertraline Dissolution Rate (mg / ml-min) Title Concentration (wt.%) Missing - Missing - Missing - Missing - Lactate 100 0.9 Missing - Ascorbic 51.0 Lactose twenty Missing - Lactate 14 3,5 1t \ u11og® 312 5,0 Ascorbic 49.5 Lactose 12.5 CaCO3 5 Lactate 14 20.9 Lecithin 5,0 Ascorbic 51.0 Lactose fifteen Missing - Lactate 14 10 PEG 3550 5,0 Ascorbic 51.0 Lactose fifteen Missing - Lactate 14 9.3 Sarti1® MSM 5,0 Ascorbic 71.0 Missing - Missing - Lactate 24 14.5 Sarti1® MSM 4.7 Missing Missing Lactose 17 CaCO3 Calcium Citrate 4.7 47 Lactate 13.1 4.3 1t ^ 11og® 191 5,0 Ascorbic 49.5 Lactose 12.5 CaCO3 1,0 Lactate 14 8.0 Mugego1® (18-99) 5,0 Ascorbic 49.5 Lactose 12.5 Missing - Lactate 14 6.4 8rap® 60 5,0 Ascorbic 51.0 Lactose fifteen Missing - Lactate 14 9.5 Ascorbyl palmitate 6.8 Missing Missing Lactose 74,2 Missing - Lactate 19 4.3 Methylparaben / propi lparaben / propyl gallate 0.5 / 0.5 / 1,0 Ascorbic 50,0 Lactose 17.5 Missing Lactate 14 11.5 1t \ u11og® 312 6.8 Aspartic 74,2 Missing - Missing - Lactate 19 5.3

Table 17-1

Example No. Core composition Osmotic coating spacing Maca core (mg) Medicine Acid Solubilizer Osmotic agent Ανίοεί mass. % MD 81 mass. % Other e Polymer Type Poly mass measures. % REO mass. % Water mass. % Shell mass (wt.% On dry matter) Salt form Mass % Type of Mass % Type of Mass % Type of Mass % sixteen 470 chlorine D 12 missing missing lact oza 66 twenty 2 missing AC 10 2,5 fifteen 15.4 17a 470 lactate 14 missing missing lact oza 65,4 19.3 1.33 missing The EU 6 4 8 one 176 470 acetate 14 Asko Rbin Nova fifty missing lact oza twenty fifteen missing Mood The EU 6 4 10 10.1 17c 470 lactate 14 Asko Rbin Nova fifty missing lact oza fifteen 21 missing missing The EU 6 4 10 10.1 17g 470 lactate 14 limo different fifty missing lact oza twenty fifteen missing Tteep The EU 6 4 10 9.9 17d 470 lactate 14 aspa ragi nova i eleven missing fruit toza 38 29.5 2,5 Aceta tSa AC 10 2,5 fifteen eleven 17th 470 lactate 14 missing 1t 5 lact oza 58.4 twenty 2.6 missing The EU 6 4 10 10 17zh 470 lactate 14 missing 1t 5 xyl IT 53.5 25 2,5 missing AC 10 2,5 fifteen 15,5 17z 470 lactate 14 Asko Rbin Nova fifty MK 5 lact oza 12.5 12.5 missing Mood The EU 6 4 10 10.5 17i 470 lactate 14 glut amine nova 10 MK 5 saha rose fifty fifteen missing Lacta tSa, Mood The EU 6 4 10 10.5 17k 470 lactate 14 aspa ragi nova i eleven MK 5 saha rose 53 fifteen Mood The EU 6 4 10 10.1 17l 470 lactate 14 asko 32 1t 5 lact 12 29th 3 CaCO3 The EU 7 3 6 15.1

131

132. -------------------------------------------------- ---, ------------------------------------ \

rbin new oza 17m 470 lactate 14 Asko Rbin Nova 32 1t 5 lact oza 12 29.5 2.6 CaCO ₃ The EU 6 4 10 10.1 17n 470 lactate 14 aspa ragi nova i eleven 1t 5 fruit toza 36 27 2,5 Aceta tSa AC 10 2,5 fifteen 10.3 17o 470 lactate 14 glyc II 26 1t 5 FRUCE TOZA 28.5 25 2,5 missing AC 10 2,5 fifteen 15.9 17p 580 lactate 11.2 Asko Rbin Nova 36.5 Triac is one 4.2 lact oza 16,2 31.1 missing Mood The EU 6 4 10 10 17p 470.5 lactate 13.9 amber 37,2 PEG 15.9 lact oza 37.9 missing missing K1ise1, 8b8 The EU 6 4 10 10 17s 536 lactate 12.1 Asko Rbin Nova 44 Sarshee one 4.4 lact oza 12 22.1 1,5 CaCO3 The EU 6 4 10 9.9 17t 470 lactate 14 Asko Rbin Nova 37 8rap 60 5 lact oza 11,4 25 2.6 CaCO3 The EU 6 4 10 9.8 17y 470 lactate 14 Asko Rbin Nova 37 Lecite in 5 lact oza 11,4 25 2.6 CaCO3 The EU 6 4 10 9.9 17f 470 lactate 14 Asko Rbin Nova 32 1t 5 lact oza 12 29.5 2.7 CaCO3 The EU 7 3 6 17 17x 470 lactate 14 Asko Rbin Nova 32 1t 5 lact oza 12 29.5 2.7 CaCO3 The EU 6 4 8 fifteen 17c 470 lactate 14 aspa ragi nova i eleven 1t 5 Fruit toza 36 27 2,5 Aceta tSa AC 10 2,5 fifteen twenty 17h 470 lactate 14 aspa ragi nova i eleven missing FRUCE TOZA 38 29.5 2,5 Aceta tSa AC 10 2,5 fifteen 10

1t = 1tlI1og 312 Sarti1 = Sarti1 MSM Tteeep = Tteeep 80

MK = monocaprilat MD. 81. = magnesium stearate K1ise1 = K1ise1 EP

PEG = polyethylene glycol 3350 Mood = Mood 52 8 L8 = sodium lauryl sulfate

EU = EU! 8-100 AC = cellulose acetate 398-10

Claims (83)

(1) if the specified dosage form is a tablet with a long release or non-disintegrating capsule with a long release, the apparatus I8P-2 is equipped with a blade rotating at a speed of 50 rpm; 1. A sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, the dosage form releasing sertraline into the medium in which it is used at a rate not exceeding 0.8 mgA / h / kg, and the specified environment in which the use is made, is either the gastrointestinal tract of a mammal, or test medium тестаη νΐΐίο, which is an ace Atomic buffer, pH 4.0 and which is 0.075M according to No. C1, and provided that the indicated dosage form (1) releases no more than 70% of the sertraline contained in it within the first hour after entering the specified medium, which is used, and (2) releases sertraline at a rate of at least 0.02 mgA / h / kg. (2) if said dosage form is a plurality of particles, said I8R-2 apparatus is equipped with a blade rotating at a speed of 100 rpm; provided that said dosage form (a) releases no more than 70% of the sertraline contained therein within the first hour after the start of testing, and (b) releases sertraline at a rate of at least 1 mgA / h. 2. The dosage form according to claim 1, where the specified sertraline is presented in the form of a free base of sertraline, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 3. The dosage form according to claim 1, where the specified mammal is a human. 4. The dosage form according to claim 1 in the form of a tablet with a matrix that remains essentially intact for a period of prolonged release. 5. The dosage form according to claim 1 in the form of a disintegrating matrix tablet. 6. The dosage form according to claim 1 in the form of a tablet with a matrix partially coated with a polymer that interferes with the release of sertraline. 7. The dosage form according to claim 1 in the form of an osmotic tablet. 8. The dosage form according to claim 1 in the form of a tablet with a hydrogel coated with a membrane membrane. 9. The dosage form according to claim 1, which is a plurality of particles. 10. The dosage form according to claim 1 in the form of diffusion-based capsules, tablets or a plurality of membrane-coated particles. 11. A sustained release dosage form suitable for administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein 133 134 this dosage form releases sertraline into the medium in which it is used at a rate not exceeding 40 mgA / h, and the specified medium in which it is used is either the gastrointestinal tract of the mammal or the test medium ίη νίίτο, which represents It is an acetate buffer, pH 4.0 and which is 0.075 M in NaCl, provided that the indicated dosage form (1) releases no more than 70% of the sertraline contained in it within the first hour after entering the specified medium, in Ora made use of, and (2) releases sertraline at a rate of at least 1 mgA / hr. 12. The dosage form according to claim 11, wherein said sertraline is presented in the form of a free base of sertraline, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 13. The dosage form according to claim 11, where the specified mammal is a human. 14. The dosage form according to claim 11 in the form of a tablet with a matrix, which remains essentially intact during the period of prolonged release. 15. The dosage form according to claim 11 in the form of a disintegrating tablet with a matrix. 16. The dosage form according to claim 11 in the form of a tablet with a matrix partially coated with a polymer that interferes with the release of sertraline. 17. The dosage form according to claim 11 in the form of an osmotic tablet. 18. The dosage form according to claim 11 in the form of a tablet with a hydrogel coated with a membrane membrane. 19. The dosage form according to claim 11, which is a plurality of particles. 20. The dosage form according to claim 11 in the form of diffusion-based tablets or a plurality of membrane-coated particles. 21. A sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, the dosage form releasing sertraline at a rate of less than 40 mgA / h, ίη νίίτο when tested for dissolution in the apparatus И8Р-2, containing 900 ml of acetate buffer, pH 4.0, which is 0.075M in NaCl, as follows: 22. The dosage form according to item 21, where the specified sertraline is presented in the form of a free base of sertraline, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 23. The dosage form according to item 21, where the specified mammal is a human. 24. The dosage form according to item 21 in the form of a tablet with a matrix, which remains essentially intact during the period of prolonged release. 25. The dosage form according to item 21 in the form of a disintegrating tablet with a matrix. 26. The dosage form according to item 21 in the form of a tablet with a matrix partially coated with a polymer that inhibits the release of sertraline. 27. The dosage form according to item 21 in the form of an osmotic tablet. 28. The dosage form according to item 21 in the form of a tablet with a hydrogel coated with a membrane membrane. 29. The dosage form according to item 21, which is a plurality of particles. 30. The dosage form according to item 21 in the form of diffusion-based tablets or a plurality of particles coated with a membrane membrane. 31. A sustained release sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, the dosage form after administration of said mammal releasing sertraline into the gastrointestinal tract of said mammal at a rate of less than 1 mgA / h for the initial period of deceleration of up to 3 hours, and then releases sertrali n at a rate of 1 to 40 mgA / h, provided that the dosage form releases no more than 70% of the sertraline contained therein within the first hour after the indicated retardation period. 32. The dosage form according to p, where the specified period of delay is up to two hours. 135 136 33. The dosage form according to p, where the release rate after the specified period of deceleration is from 1 to 30 mgA / h 34. The dosage form according to p, where the specified sertraline is presented in the form of a free base of sertraline, sertraline hydrochloride, aspartate sertraline, sertraline acetate or sertraline lactate. 35. The dosage form according to p, where the specified mammal is a human. 36. A time-delayed sustained release dosage form suitable for administration to a mammal, having an initial time-delay period of up to 3 hours, including sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, the dosage form being testing it for dissolving ίη νίΙΐΌ in an I8R-2 apparatus containing 900 ml of acetate buffer, pH 4.0, which is 0.075 M according to No. C1, releases sertraline at a rate of less than 1 mgA / h for a period corresponding to the indicated period of deceleration, and then releases sertraline at a rate of 1 to 40 mgA / h, provided that this dosage form releases no more than 70% of the remaining sertraline contained in it, within the first hour after the indicated slowdown period. 37. The dosage form according to clause 36, where the specified period of delay is up to two hours. 38. The dosage form according to clause 36, where the release rate after the specified period of slowdown is from 1 to 30 mgA / h 39. The dosage form according to clause 36, where the specified sertraline is presented in the form of a free base of sertraline, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 40. The dosage form according to clause 36, where the specified mammal is a human. 41. The dosage form of claim 36 is in the form of a tablet. 42. The dosage form of claim 36, which is a plurality of particles. 43. A dosage form with a spatial delayed release followed by a sustained release, suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form after administration by said mammal releases sertraline in the stomach of said mammal at a rate component less than 1 mgA / h, and after passing into the small intestine of the specified mammal carries out prolonged excretion bozhdenie at a rate of from 1 to 40 mgA / hr, provided said dosage form releases not more than 70% of the sertraline contained therein within the first hour after passing into said mammal's small intestine. 44. The dosage form according to item 43, where the onset of prolonged release is initiated by pH. 45. The dosage form according to claim 44, comprising a sustained release dosage form coated with a polymer that prevents the release of sertraline at pH of the stomach, but which is permeable to sertraline at pH of the small intestine. 46. A dosage form according to claim 44, wherein said sustained release dosage form is a plurality of particles. 47. A dosage form according to claim 44, wherein said sustained release dosage form is a tablet. 48. The dosage form according to item 43, the action of which is initiated by enzymes. 49. The dosage form of claim 48, comprising a sustained release dosage form coated with a membrane containing a hydrophobic fluid trapped in its pores, said hydrophobic fluid being substantially impermeable to water and sertraline, but capable of being altered by enzymatic degradation so that said membrane becomes substantially permeable to water and sertraline when said dosage form moves into the lumen of the small intestine. 50. The dosage form of claim 48, wherein said sustained release dosage form is a plurality of particles. 51. The dosage form of claim 48, wherein said sustained release dosage form is a matrix. 52. The dosage form according to item 43, wherein said sertraline is presented in the form of a free base of sertraline, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 53. The dosage form according to item 43, where the specified mammal is a human. 54. A sustained release dosage form that is triggered by a pH suitable for oral administration to a mammal, having an initial delay period before the start of a sustained release, including sertraline or 137 138 its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, and this dosage form, when tested with ίη νίΙΐΌ in the I8P-2 apparatus, releases sertraline in 0.1N. HC1 at a rate of less than 1 mgA / h for 1 h and then releases sertraline into a phosphate buffer, pH 6.8, containing 1% polysorbate-80, at a rate of 1 to 40 mgA / h, provided that this dosage form releases no more than 70% of the remaining sertraline contained therein within the first hour after the indicated delay. 55. The dosage form according to claim 54, comprising a sustained release dosage form coated with a coating comprising a polymer that prevents the release of sertraline in said HC1 at a rate exceeding 1 mgA / h, but which is permeable to sertraline and makes it possible prolonged release of sertraline in the specified phosphate buffer. 56. The dosage form according to claim 55, wherein said sustained release dosage form is a plurality of particles. 57. The dosage form of claim 55, wherein said sustained release dosage form is a tablet. 58. The dosage form according to claim 54, wherein said sertraline is in the form of a free base of sertraline, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 59. The dosage form according to claim 54, wherein said mammal is a human. 60. A sustained release dosage form that is initiated by enzymes, suitable for oral administration to a mammal, having an initial delay period before the beginning of a sustained release, including sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and this dosage form when tested приη νίίΐΌ in the device И8Р releases sertraline in 0,1n. HC1 at a rate of less than 1 mgA / h for a period of 1 h and then releases sertraline at a rate of 1 to 40 mgA / h into phosphate buffer, pH 6.8, containing 1% polysorbate 80, and in the presence of an enzyme suitable for initiating the onset of said sustained release, provided that this dosage form releases no more than 70% of the remaining sertraline contained therein within the first hour after said retardation. 61. The dosage form of claim 60, comprising a sustained release dosage form coated with a membrane containing a hydrophobic liquid trapped in its pores, said hydrophobic liquid being substantially impermeable to water and sertraline in said acid, but is capable of varying in said buffer by enzymatic degradation in the presence of said enzyme so that said membrane becomes substantially permeable to water and sertraline. 62. The dosage form of claim 60, wherein said sustained release dosage form is a plurality of particles. 63. The dosage form according to claim 60, wherein said sustained release dosage form is a tablet. 64. The dosage form of claim 60, wherein said sertraline is in the form of a free base of sertraline, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 65. The dosage form of claim 60, wherein said mammal is a human. 66. A sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, when administered as a specific dose to said mammals, results in a maximum plasma sertraline concentration, C _max , which is less than 80% of the C _max obtained by oral administration of an equal dose of sertraline in the form of an immediate-release bolus, when provided that the sustained release dosage form (1) releases no more than 70% of the sertraline contained therein within the first hour after administration, and (2) releases sertraline at a rate of at least 1 mgA / h . 67. The dosage form according to claim 66, which provides the general effect of the drug on the blood, which does not decrease in the same proportion as Smaks. 68. The dosage form of claim 66, wherein said sertraline is in the form of a free base of sertraline, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate. 69. The dosage form according to p, where the specified mammal is a human. 70. The dosage form of claim 66 is in the form of a tablet. 71. The dosage form of claim 66, which is a plurality of particles. 139 140 72. The dosage form according to p, which is a dosage form with a slow release followed by a prolonged release, giving a retardation period of up to three hours before the start of a prolonged release, wherein said dosage form releases sertraline at a rate of not more than 1 mgA / h, during the indicated period of deceleration. 73. The dosage form of claim 72, wherein said retardation is a time delay. 74. The dosage form of claim 72, wherein said retardation is spatial retardation. 75. A method of treating psychiatric disease, premature ejaculation, chemical dependence, a premenstrual dysphoria disorder, or obesity, in which, if necessary, a mammal is administered, including a human patient, a therapeutically effective amount of sertraline in a dosage form with a long release for oral administration introduction according to claim 1. 76. A method of treating a psychiatric disease, premature ejaculation, chemical dependence, a premenstrual dysphoria disorder, or obesity, in which, if necessary, a mammal is administered, including a human patient, a therapeutically effective amount of sertraline in a dosage form with an extended release for oral administration introduction according to claim 11. 77. A method of treating a psychiatric disease, premature ejaculation, chemical dependence, a premenstrual dysphoria disorder, or obesity, in which, if necessary, a mammal is administered, including a human patient, a therapeutically effective amount of sertraline in a sustained release dosage form for oral administration introduction according to item 21. 78. A method of treating a psychiatric disease, premature ejaculation, chemical dependence, premenstrual dysphoria disorder, or obesity, in which, if necessary, a mammal, including a human patient, is administered a therapeutically effective amount of sertraline in a dosage form with a delayed release followed by sustained release for oral administration according to p. 79. A method of treating a psychiatric disease, premature ejaculation, chemical dependence, a disorder associated with premenstrual dysphoria, or obesity, in which, if necessary, such a treatment is administered to a mammal, including a human patient, a therapeutically effective amount of sertraline in a dosage form with a delayed release followed by sustained release for oral administration according to clause 36. 80. A method of treating psychiatric disease, premature ejaculation, chemical dependence, a disorder associated with premenstrual dysphoria, or obesity, in which, if necessary, such a treatment is administered to a mammal, including a human patient, a therapeutically effective amount of sertraline in a dosage form with a delayed release followed by sustained release for oral administration according to item 43. 81. A method of treating psychiatric disease, premature ejaculation, chemical dependence, a disorder associated with premenstrual dysphoria, or obesity, in which, if necessary, such a treatment is administered to a mammal, including a human patient, a therapeutically effective amount of sertraline in a dosage form with a delayed release followed by sustained release for oral administration according to item 54. 82. A method of treating a psychiatric disease, premature ejaculation, chemical dependence, premenstrual dysphoria disorder, or obesity, in which, if necessary, a mammal, including a human patient, is administered a therapeutically effective amount of sertraline in a dosage form with a delayed release followed by sustained release for oral administration according to claim 60. 83. A method of treating a psychiatric disease, premature ejaculation, chemical dependence, a disorder associated with premenstrual dysphoria, or obesity, in which, if necessary, such a treatment is administered to a mammal, including a human patient, a therapeutically effective amount of sertraline in a dosage form with a delayed release followed by sustained release for oral administration according to claim 66.